Methods of identifying critically ill patients at increased risk of development of organ failure and compounds for the treatment hereof

ABSTRACT

The present invention relates to compounds for treatment that protects the endothelium, prevents pathologic thrombus formation in the microcirculation and preserves platelet number and function and thus may be related to minimizing or preventing development of organ failure, including multiple organ failure (MOF), and, hence, death in critically ill patients by administration of agent(s) limiting the platelets ability to aggregate and form clots and/or by agents modulating/preserving endothelial integrity and/or by agent(s) increasing the rate of thrombus lysis, and Another aspect of the invention related to by a cell-based whole blood viscoelastical haemostatic assay identifying critically ill patients at increased risk of development of organ failure, including multiple organ failure (MOF) and death.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/142,935 filed Jun. 30, 2011, which is the U.S. National Phase ofPCT/DK2009/050357 filed Dec. 30, 2009, which claims priority of DanishPatent Application PA 2008 01844 filed Dec. 30, 2008, and U.S.Provisional Application 61/161,487 filed Mar. 19, 2009.

All patent and non-patent references cited in the application, or in thepresent application, are also hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to a novel use of compounds that protectthe endothelium, prevent pathologic thrombus formation in themicrocirculation and/or preserve platelet number and function in thecirculation and thus may be related to minimizing or preventingdevelopment of organ failure, including multiple organ failure (MOF),and, hence, death in critically ill patients by administration ofagent(s) limiting the platelets ability to aggregate and form clotsand/or by agents modulating/preserving endothelial integrity and/or byagent(s) increasing the rate of thrombus lysis, and methods of by acell-based whole blood viscoelastical haemostatic assay identifyingcritically ill patients at increased risk of development of organfailure, including multiple organ failure (MOF) and death.

BACKGROUND OF THE INVENTION

Platelets are anucleate fragments of megakaryocyte cytoplasm. They arepivotal for haemostatic plug formation, both by forming the initialthrombus at the site of vascular lesion and by providing template forcoagulation protein assembly with subsequent thrombin generationresulting in conversion of fibrinogen to fibrin which interacts with theactivated platelets through the GPIIb/IIIa receptor forming thehaemostatic clot [Roberts et al. 2006] and by maintaining vascular wallintegrity [Nachman and Rafii 2008]

Under physiologic conditions, platelet aggregation and haemostasis isprevented by the vascular endothelium. The endothelium provides aphysical barrier and secretes platelet inhibitory products, such as prostacycline (PGI2) and nitric oxide (NO). These compounds regulate theadhesiveness of platelets and the activation state of the plateletreceptor GPIIb/IIIa in a paracrine way and also maintain the endotheliumin a quiescent state through autocrine mechanisms [Zardi et al 2005].

With endothelial activation or injury (trauma, critical illness likesepsis, atherosclerosis), platelets adhere to the endothelium orsubendothelium, respectively. This adhesion activates platelets, causesa shape change and a release reaction where ADP is released (which is apotent platelet agonist). The platelet membrane integrin receptor,GPIIb/IIIa, becomes activated. Fibrinogen binds to this receptor,effectively cross-linking platelets to form a platelet plug. Duringplatelet activation, thromboxane A2 is formed from hydrolysis ofphospholipids (especially phosphatidylcholine) in the platelet membrane.This is an important platelet agonist, recruiting other platelets andactivating them, thus promoting further platelet aggregation. Thrombusformation is a problem in many clinical situations, mainlycardiovascular diseases where platelets are also involved inatherothrombotic disease where they support development of thrombusformation on atherosclerotic plaques eventually resulting in occlusionof vessels and cell death, exemplified by acute myocardial infarction[De Meyer et al. 2009].

In Intensive Care Unit (ICU) patients and especially in sepsis,pathologic thrombus formation attributed to inflammation inducedendothelial dysfunction and platelet activation is likely to be one ofthe main causes of morbidity and mortality. Thus, almost half of allpatients with sepsis, major trauma or other critical illness presentwith or develop thrombocytopenia. In critically ill patients,thrombocytopenia upon arrival to the intensive care unit (ICU), iscommon and is associated with increased mortality [Moreau et al. 2009],longer ICU stays, a higher incidence of bleeding events, greatertransfusion requirements and regardless of the cause, thrombocytopeniaor declining platelet count is an independent predictor of multi organfailure (MOF) [Nguyen and Carcillo 2006] and ICU mortality [Levi andLowenberg 2008]. The pathogenesis of low or declining platelet count incritically ill patients is multifactorial and involve e.g., bleeding,sepsis, thrombotic microangiopathy including disseminated intravascularcoagulation (DIC) and immune or drug-induced thrombocytopenia [Nguyenand Carcillo 2006; Levi and Lowenberg 2008].

Thrombocytopenia and a decline in platelet count may reflect the samepathophysiologic disturbances seen in sepsis, disseminated intravascularcoagulation (DIC), vitamin deficiencies, macrophage activation,drug-induced toxicity, liver disease, haematologic disorders, massivetransfusions, immune mediated thrombocytopenia and unidentified factorsref [Moreau et al. 2007]. The increased mortality in critically patientswith thrombocytopenia is complex and relates also in part to developmentof progressive organ failure accompanied by a decline in platelet count,thrombocytopenia associated multi organ failure (TAMOF). TAMOF is athrombotic microangiopathic syndrome that can be defined by a spectrumof pathology that includes disseminated intravascular coagulation (DIC)and secondary thrombotic microangiopathy (TMA) [Nguyen and Carcillo2006].

A common feature for TAMOF is the progressive decline in platelet countrelated to systemic profound coagulation activation, down-regulation ofboth fibrinolysis and natural anticoagulants resulting in plateletconsumption and microvascular thrombus formation where the plateletsplay an integral role [Nguyen and Carcillo. 2006]. A non-exhaustive listof conditions associated with TAMOF is presented in Table 1.

Table 1: Conditions Associated with Organ Failure, Including MOF andTAMOF

-   Cancer-   Transplantation (solid organs, haematopoietic stem cells)-   Cardiovascular surgery/cardiopulmonary bypass/extracorporeal    membrane oxygenation (ECMO)-   Vascular surgery-   Autoimmune disease-   Systemic infection-   Vasculitis-   Exposure to toxins-   Cyclosporine A therapy-   FK 506 therapy-   Chemotherapy-   Radiation-   Ticlopidine treatment-   Hemolytic Uremic Syndrome variant syndromes.-   Trauma (e.g. polytrauma, neurotrauma, fat embolism)

Non-exhaustive list of conditions associated with TAMOF-DIC is presentedin Table 2.

Table 2: Clinical Conditions that May be Associated with DisseminatedIntravascular Coagulation

-   Sepsis/severe infection (any microorganism)-   Malignancy    -   Myeloproliferative/lymphoproliferative malignancies    -   Solid tumors    -   Metastasis-   Trauma (e.g. blunt/penetrating trauma, polytrauma, neurotrauma, fat    embolism, burn trauma)-   Obstetrical calamities    -   Amniotic fluid embolism    -   Abruptio placentae-   Organ destruction (e.g. severe pancreatitis)-   Severe toxic or immunologic reactions    -   Snake bites    -   Recreational drugs    -   Transfusion reactions    -   Transplant rejection (graft vs. host disease, host vs. graft        disease)-   Vascular abnormalities    -   Kasabach-Merritt syndrome    -   Large vascular aneuysms-   Severe hepatic failure-   Embolism    -   Thromboembolism    -   Cholesterol embolism    -   Fat embolism    -   Air embolism    -   Septic embolism    -   Tissue embolism    -   Foreign body embolism    -   Amniotic fluid embolism

Standard treatment in the intensive care unit of critically ill patientswith or without thrombocytopenia focuses on:

1. Identification and specific treatment of the underlying disordercausing the patients condition, and2. support of vital organs in case of failure exemplified by ventilatorysupport, haemodialysis, vasopressor treatment, parenteral nutrition,fluid support, corticosteroids, tight glycemic control, administrationof blood products and others generally referred to as intensive caremanagement [Bick R. 1996, Bick R. 1998].

Furthermore, the treatment may include attenuation of the procoagulantcondition by systemic administration of agents which decrease enzymaticcoagulation activation such as:

1. Heparins (low molecular weight heparin (LMWH), unfractioned heparin(UFH))2. Thrombin inhibitors

3. Antithrombin

4. Tissue factor pathway inhibitor (TFPI)

5. Activated Protein C

have been evaluated and especially in critically ill patients withsevere sepsis which carries a high mortality (>50%).

Ad 1. Heparins

Meta-analysis suggests that venous thromboembolism (VTE) prophylaxiswith an LMWH (including fondaparinux) or UFH is effective in reducingthe rate of deep venous thrombosis (DVT), but this benefit did notextend to enhanced protection against pulmonary embolism (PE).Additionally, LMWH and UFH had similar bleeding outcomes and hence VTEprophylaxis with heparins is standard therapy in critically ill medicaland surgical patients, also in the ICU. It is recommended that, onadmission to the ICU, all patients are assessed for their risk of VTE,and that most receive thromboprophylaxis (Grade 1A) [Kanaan et al. 2007,Geerts et al. 2008].

Ad 2. Thrombin Inhibitors

Direct thrombin inhibitors (DTIs) act as anticoagulants (delaying bloodclotting) by directly inhibiting the enzyme thrombin. There are twotypes of DTIs, dependent on their interaction with the thrombinmolecule. Bivalent DTIs (hirudin and analogs) bind both to the activesite and exosite 1, while univalent DTIs bind only to the active site.Bivalent: Hirudin, Bivalirudin, Lepirudin, Desirudin; Univalent:Argatroban, Melagatran, Dabigratan

Ad 3. Antithrombin

A Cochrane analysis included 20 randomized trials with a total of 3458participants; 13 of these trials had high risk of bias. When combiningall trials, AT III did not statistically significantly reduce overallmortality compared with the control group (RR 0.96, 95% CI 0.89 to 1.03;no heterogeneity between trials). A total of 32 subgroup and sensitivityanalyses were carried out. Analyses based on risk of bias, differentpopulations, and the role of adjuvant heparin gave insignificantdifferences. AT III reduced the multiorgan failure score among survivorsin an analysis involving very few patients. AT III increased bleedingevents (RR 1.52, 95% CI 1.30 to 1.78). ATIII therapy of critically illpatients is not recommended [Afshari et al. 2008].

Ad 4. TFPI

Efficacy and safety of tifacogin (recombinant tissue factor pathwayinhibitor) in severe sepsis was evaluated in a randomized controlledtrial (OPTIMIST) encompassing 1754 patients. All cause mortality in theTFPI treated group was 34.2% vs 33.9% in placebo treated patients,p=0.88. Tifacogin administration was associated with an increase in riskof bleeding, irrespective of baseline INR and there is currently noindication for TFPI treatment of patients with severe sepsis [Abraham etal. 2003].

Ad 5. Activated Protein C

The PROWESS study in patients with severe sepsis was prematurely stoppedat the second interim analysis because of a significant reduction inmortality in the APC treated patients [Bernard et al 2001]. A totalnumber of 1728 patients were included and randomized in this study, ofwhich 1690 were eligible for analysis. Of these patients, 840 wererandomized to receive recombinant human APC at a dose of 24 mg/kg/h for96 h, and 850 patients received placebo. Mortality was 24.7% in the APCgroup as compared with 30.8% in the placebo group (relative riskreduction 19.4 percentages, 95% confidence interval 6.6-30.5). Theseries of negative trials in specific populations of patients withsevere sepsis performed after the PROWESS study has added to thescepticism regarding the use of APC [Marti-Carvajal et al. 2007].Furthermore, on the basis of the ADDRESS study, treatment with APC seemsnot to be indicated in patients with sepsis and a relatively low diseaseseverity [Levi M 2008]. No consensus regarding the use of APC inpatients with severe sepsis exists today.

Despite all these initiatives, many patients do not achieve homeostasis,continue to bleed, become immunodeficient, loose endothelial wallintegrity (the endothelial wall becomes activated), and/or develop MOFand/or TAMOF and die. Thus, there remains a need for a method oftreatment for critically ill patients; a method which may includetreatment and/or prevention of development of organ failure such as MOFand/or TAMOF, and/or arrest bleeding, and/or prevent immunodeficiency,and/or preserving endothelial integrity in critically/acutely illpatients and furthermore, there is a need for a composition that may beused in this method.

BRIEF DESCRIPTION OF THE INVENTION

Surprisingly, the present inventors have found that the administrationof a combination of a platelet inhibitor and at least one othercompound, the at least one other compound being selected amongst acompound capable of modulating/preserving the endothelial integrity, acompound capable of augmenting the fibrinolytic activity, or a TAFIainhibitor is beneficial in the treatment and/or prevention of organfailure, wherein organ failure is defined as altered organ function inan acutely ill patient. The patient may require medical intervention toachieve homeostasis; and organ failure includes as used herein MOF andTAMOF, in at least one organ, such as in at least two, three, four orfive organs.

Furthermore, a combination of compounds that target both the plateletsand endothelium to obtain a synergistic effect of the compounds ascompared to only targeting either the platelets or the endothelium is anaspect of the present invention. Also, it is an aspect that by combiningthe treatments, a lower level/dosage of the compound(s) to beadministered may be required with the advantage of reduced risk ofpossible adverse events.

The theory behind the current invention is that thrombocytopenia and/ordeclining platelet count in critical illness:

-   -   1. Is a consequence of enhanced platelet activation, aggregation        and thrombus formation in the microvasculature and hence a        strong marker of increased risk of microthrombi-ischemia-induced        organ failure and/or    -   2. Induces endothelial dysfunction through lack of and/or        dysregulated paracrine effects of platelets released mediators        on endothelial integrity and/or activation state and/or    -   3. Results in immunodeficiency through an integrated effect of        platelets on cells of the innate and adpative immune system and        hence on the inflammatory response.        The thrombocytopenia observed in many ICU patients is thus a        marker and/or driver of profound dysregulation attributed to        exaggerated microthrombi formation, endothelial activation,        dysfunction and integrity loss and immunodeficiency through        compromised platelet function on a per cell basis and through a        general reduction in platelets mass, all contributing to        pathologies, exemplified by organ failure, in ICU patients.

As stated above, the inventors propose that thrombocytopenia per seresults in immunodeficiency through loss of platelet-mediated immunefunctions. Due to significant redundancy, the thrombocytopeniaassociated immunodeficiency (TAID) may be aggravated when other limbs ofthe immune system are compromised, as in critically ill patients. TAIDin critical illness may thus in part explain the negative predictivevalue of low or declining platelet count and the administration of thecompounds, combinations of same and pharmaceutical compositionsdescribed herein may also be beneficial to this novel aspect ofthrombocytopenia.

Under physiologic conditions, platelet aggregation and haemostasis isprevented by the vascular endothelium. The endothelium provides aphysical barrier and secretes platelet inhibitory products, such asprostacyclin (PGI2) and nitric oxide (NO). These compounds regulate theadhesiveness of platelets and the activation state of the plateletreceptor GPIIb/IIIa in a paracrine way and also maintain the endotheliumin a quiescent state through autocrine mechanisms [Zardi et al 2005].Without being bound by theory it is suggested that preservation ofnormal circulating platelet count may protect against bleeding alonethrough these paracrine mechanisms, despite concomitant directinhibition of platelet aggregation and clot formation [Goerge et al.2008.]

The present invention relates in a first aspect to pharmaceuticalcompositions comprising one or more of any of the compounds mentionedherein below, such as one compound, such as at least two compounds, suchas at least three compounds. When using more than one compound, thecompounds may be selected from the same group of compounds, or morepreferably the at least two compounds may be selected from differentgroups of compounds. Accordingly, in one embodiment one compound is aplatelet inhibitor and the at least one other compound is a compoundcapable of modulating/preserving the endothelial integrity, a compoundcapable of augmenting the fibrinolytic activity, or a TAFIa inhibitor.In another embodiment, one compound is a compound capable ofmodulating/preserving the endothelial integrity and the at least oneother compound is a compound capable of augmenting the fibrinolyticactivity, or a TAFIa inhibitor. In a third embodiment one compound is acompound capable of augmenting the fibrinolytic activity and the atleast one other compound is a TAFIa inhibitor.

Preferably the one or more compounds are a platelet inhibitor and acompound capable of modulating/preserving the endothelial integrity,more preferably an antithrombotic compound even more preferably aGPIIb/IIIa inhibitor and PGI2.

Another aspect of the invention relates to the use of a pharmaceuticalcomposition as described herein for treatment and/or prevention organfailure wherein organ failure is defined as altered organ function in anacutely ill patient requiring medical intervention to achievehomeostasis; organ failure includes as used herein MOF and TAMOF, in atleast one organ, such as in at least two, three, four or five organs.

Still another aspect of the invention relates to the use of thepharmaceutical composition as described herein for prevention ortreatment of organ failure wherein organ failure is defined as alteredorgan function in an acutely ill patient requiring medical interventionto achieve homeostasis; organ failure includes as used herein MOF andTAMOF, in at least one organ, such as in at least two, three, four orfive organs wherein the organs are selected from the group consisting ofcardiovascular, respiratory, renal, haematological, neurological,gastrointestinal and hepatic organs.

Another aspect of the invention relates to a composition comprising oneor more compounds selected from the group consisting of plateletinhibitors, compounds capable of modulating/preserving the endothelialintegrity, compounds capable of augmenting the fibrinolytic activity, orTAFIa inhibitors for use in treatment and prevention of organ failurewherein organ failure is defined as altered organ function in an acutelyill patient requiring medical intervention to achieve homeostasis; organfailure includes as used herein MOF and TAMOF, in at least one organ,such as in at least two, three, four or five organs.

Another aspect of the invention relates to a composition comprising aplatelet inhibitor and a compound capable of modulating/preservingendothelial integrity for use in the treatment and prevention of organfailure wherein organ failure is defined as altered organ function in anacutely ill patient requiring medical intervention to achievehomeostasis; organ failure includes as used herein MOF and TAMOF, in atleast one organ, such as in at least two, three, four or five organs.

Another aspect of the invention relates to a composition comprising oneor more compounds selected from the group consisting of plateletinhibitors, compounds capable of modulating/preserving the endothelialintegrity, compounds capable of augmenting the fibrinolytic activity, orTAFIa inhibitors for use in treatment and prevention of organ failurewherein organ failure is defined as altered organ function in an acutelyill patient requiring medical intervention to achieve homeostasis; organfailure includes as used herein MOF and TAMOF, in at least one organ,such as in at least two, three, four or five organs.

Yet another aspect of the invention relates to a composition comprisinga platelet inhibitor and a compound capable of modulating/preservingendothelial integrity for use in the treatment and prevention of organfailure wherein organ failure is defined as altered organ function in anacutely ill patient requiring medical intervention to achievehomeostasis; organ failure includes as used herein MOF and TAMOF, in atleast one organ, such as in at least two, three, four or five organs.

Another aspect of the invention relates to a compound as describedherein or a composition as described herein for prevention or treatmentof organ failure, wherein organ failure is defined as altered organfunction in an acutely ill patient requiring medical intervention toachieve homeostasis; organ failure includes as used herein MOF andTAMOF, in at least one organ, such as in at least two, three, four orfive organs, wherein the organ failure is due to systemic inflammationor due to severe infections or due to sepsis or due to systemicinflammatory response syndrome (SIRS) and/or compensatoryanti-inflammatory response syndrome CARS or due to coagulopathy or dueto trauma and/or burns or due to malignant diseases such ashaematological malignancies, solid tumours and metastatic tumours or dueto ischemia or due to cardiovascular thromboembolic diseases or due tointoxication.

In a further aspect the invention relates to one or more plateletinhibitors for prevention or treatment of organ failure wherein organfailure is defined as altered organ function in an acutely ill patientrequiring medical intervention to achieve homeostasis; organ failureincludes as used herein MOF and TAMOF, in at least one organ, such as inat least two, three, four or five organs.

In a particular embodiment the organ failure is due to sepsis or due tomalignant diseases such as solid tumours, haematological malignanciesand metastatic tumours or the systemic inflammatory response syndromeand compensatory anti-inflammatory response syndrome, accompanyingtrauma.

In a further particular embodiment the organ or organs, which aresubject to failure are selected from the group consisting ofcardiovascular, respiratory, renal, haematological, neurological,gastrointestinal and hepatic organs, such as heart, liver, lungs, gut,kidneys, spleen, and brain.

In a still further aspect the invention relates to a one or morecompounds capable of modulating/preserving endothelial integrity forprevention or treatment of organ failure wherein organ failure isdefined as altered organ function in an acutely ill patient requiringmedical intervention to achieve homeostasis; organ failure includes asused herein MOF and TAMOF, in at least one organ, such as in at leasttwo, three, four or five organs.

A further aspect of the invention relates to a method of treating orpreventing organ failure, including multi organ failure, defined asaltered organ function in an acutely ill patient requiring medicalintervention to achieve homeostasis; organ failure includes as usedherein MOF and TAMOF comprising administering one or more compoundsselected from the group consisting of platelet inhibitors, compoundscapable of modulating/preserving the endothelial integrity, compoundscapable of augmenting the fibrinolytic activity, or TAFIa inhibitors.

Another aspect of the invention relates to the use of one or morecompounds selected from the group consisting of platelet inhibitors,compounds capable of modulating/preserving the endothelial integrity,compounds capable of augmenting the fibrinolytic activity, or TAFIainhibitors in the manufacture of a medicament for the treatment orprevention of organ failure, including multi organ failure, defined asaltered organ function in an acutely ill patient requiring medicalintervention to achieve homeostasis; organ failure includes as usedherein MOF and TAMOF.

Another aspect of the invention relates to a pharmaceutical compositionfor treating or preventing organ failure, including multi organ failure,defined as altered organ function in an acutely ill patient requiringmedical intervention to achieve homeostasis; organ failure includes asused herein MOF and TAMOF comprising one or more compounds selected fromthe group consisting of platelet inhibitors, compounds capable ofmodulating/preserving the endothelial integrity, compounds capable ofaugmenting the fibrinolytic activity, or TAFIa inhibitors as an activeingredient.

In another particular embodiment the organ failure is due to reperfusioninjury following ischemia.

In another aspect the invention relates to a compound capable ofaugmenting the fibrinolytic activity in whole blood for prevention ortreatment of organ failure, wherein organ failure is defined asmicrothrombosis in at least one organ, such as in at least two, three,four or five organs.

In yet another aspect the invention relates to a thrombin activatablefibrinolysis inhibitor (TAFI) an inhibitor for prevention or treatmentof organ failure, wherein organ failure is defined as microthrombosis inat least one organ, such as in at least two, three, four or five organs.

A further aspect relates to the use of a combination of compounds and/orcompositions as herein described for treatment of critically illpatients by the preservation of platelet count, whereby the patientsuffers less risk of becoming immunodeficient.

Thus the use of the pharmaceutical composition as herein disclosed forthe preservation of platelet number and/or function in a critically illpatient requiring medical intervention to achieve homeostasis is also anaspect of the present invention.

Another aspect of the present invention relates to the use of thecompounds and/or compositions as herein described for immunostimulatingpurposes, the immunostimulation being direct and/or indirect.

Yet another aspect of the invention relates to a method of diagnosing,monitoring or determining the likelihood of a organ failure includingmulti organ failure (MOF) in a critical ill human being, wherein saidmethod is capable of identifying critical ill human beings who have asignificantly increased risk of developing organ failure, including MOF,said method comprising the steps of

-   -   i) determining at least one of the viscoelastical values R,        Angle and MA by thromboelastography (TEG) or equivalent        parameters identified by thromboelastometry in a whole blood        sample from the human being critically ill, such as in a        citrated whole blood sample, such as in a citrated whole blood        sample activated by kaolin, such as in a citrated whole blood        sample activated by tissue factor, such as in a native whole        blood sample, such as a native whole blood sample activated by        kaolin, such as in a citrated whole blood sample activated by        tissue factor    -   ii) comparing said value with a predetermined cutoff value, said        cutoff value being an equivalent to a cutoff value determined by        TEG in a citrated whole blood sample activated by kaolin wherein        said cutoff value is        -   a) R higher than 8.0 minutes, such as higher than 8.5            minutes, or lower than 4.0 minutes, such as lower than 3.0            minutes,        -   b) Angle lower than 55°, such as lower than 52°, or higher            than 78°, such as higher than 80°, and        -   c) MA lower than 51 mm, such as lower than 50 mm, or higher            than 69 mm, such as higher than 72 mm            wherein an R-value higher or lower than the cutoff value            and/or an Angle-value higher or lower than the cutoff value            and/or a MA higher or lower than the cutoff value is            indicative of a significantly increased risk of developing            organ failure as compared to a human being wherein neither            R, Angle-value or MA is higher or lower than the cutoff            value.

The method allows for the identification of critically ill patients witha significantly increased risk of development organ failure, includingMOF, and 30-day mortality earlier than conventional coagulation analysesexemplified by activated partial thromboplastin time (APTT), prothrombintime (PT), platelet count and D-dimer.

Additional aspects of the present invention and particular embodimentswill be apparent from the description below, as well from the appendedclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Recording haemostatic activity using TEG assay.

FIG. 2: MultiPlate continuously records platelet aggregation. Theincrease of impedance by the attachment of platelets onto the Multiplatesensors is transformed to arbitrary aggregation units (AU) and plottedagainst time.

FIG. 3: Comparison of baseline TEG values with samples obtained after60- and 120 min of flolan infusion.

FIG. 4: Comparison of baseline Multiplate values with samples obtainedafter 60- and 120 min of flolan infusion.

DETAILED DESCRIPTION OF THE INVENTION

Interventions aiming at reducing/inhibiting the platelets ability toparticipate in the clot building process (eg. the administration ofplatelet inhibitors) will prohibit or reduce development of thrombusformation in the microvasculature and therefore reduce endothelialactivation, will increase, preserve and/or reduce the fall in thecirculating platelet count and therefore improve endothelial integrityand/or limit and/or avoid thrombocytopenia associated immunodeficiencyand hence, limit and/or prevent development of organ failure includingMOF.

Furthermore, interventions aiming at modulating/preserving endothelialintegrity (keeping the endothelium in a quiescent inactivatedanti-coagulant state, eg. by the administration of endothelialmodulators) will reduce endothelial activation and improve endothelialintegrity and therefore prohibit and/or reduce development of thrombusformation in the microvasculature which will increase and/or preservecirculating platelet count and avoid thrombocytopenia associatedimmunodeficiency and hence, limit and/or prevent development of organfailure including MOF.

Also, interventions aiming at increasing the fibrinolysis (eg. theadministration of pro-fibrinolytics) will reduce clot stability throughenhanced fibrinolysis and thereby reduce or prohibit development ofthrombus formation in the microvasculature and therefore, through theabove mentioned effects on endothelial cells and immune function, limitand/or prevent development of organ failure including MOF.

In addition, interventions aiming at reducing the activity of TAFIa (eg.the administration of TAFIa-inhibitors) will reduce clot stabilitythrough enhanced fibrinolysis and thereby reduce or prohibit developmentof thrombus formation in the microvasculature and therefore, through theabove mentioned effects on endothelial cells and immune function, limitand/or prevent development of organ failure, including MOF.

Finally, interventions aiming at reducing/inhibiting the plateletsability to participate in the clot building process (plateletinhibitors) and/or modulating/preserving endothelial integrity(endothelial modulators) and/or increasing the fibrinolytic activity(pro-fibrinolytics) and/or reducing the activity of TAFIa(TAFIa-inhibitors) in any combination will reduce clot stability andthereby reduce or prohibit development of thrombus formation in themicrovasculature and therefore, through the above mentioned effects onendothelial cells and immune function, limit and/or prevent developmentof organ failure including MOF.

Accordingly, the present invention relates to compounds for a newtreatment modality for critically ill patients, in particular patientshaving acquired or at increased risk of development of organ failure,including MOF, such as TAMOF or any condition associated with systemicinflammation.

Given the above mentioned association between critical illness withimminent or manifest organ failure and platelet activation and/or loss,endothelial activation and/or dysregulation and immunodeficiency and/ordysregulation, interventions that simultaneously

-   -   1. Modulate and/or preserve endothelial integrity by keeping the        endothelium in a quiescent inactivated anti-coagulant state        (endothelial modulators, described herein below); and    -   2. Reduce and/or inhibit the platelets ability to participate in        the clot building process (platelet inhibitors, described herein        below); or    -   3. Enhance fibrinolysis and thereby dissolve already formed        microthrombi or prevent formation of microthrombi in the        microcirculation (pro-fibrinolytics); or    -   4. Inhibit thrombin-activatable fibrinolysis inhibitor (TAFI)a        and thereby enhance fibrinolysis (TAFIa-inhibitors)        should be used to prevent and/or cure imminent and/or manifest        organ failure and/or serve to induce/preserve homeostasis in        critically ill patients. These patients may have any condition        associated with systemic inflammation (conditions suitable for        the invention, described herein below).

A further aspect relates to preserving/upholding the platelet countand/or platelet function in a subject/patient. The patient may be acritically ill patient. Such a patient may be in the need of medicalintervention to achieve homeostasis. By preserving the platelet count,the competency of the platelets as immunocompetent cells is preservedand the immunodeficiency typically observed in patients and especiallyin critically ill patients is hereby avoided. By upholding or preservingthe platelet count is understood an action that aims at maintaining theplatelet count within normal levels ie. a level above a level defined asthrombocytopenic and below a level indicative of thrombocytosis. Thusthe level may be a level such as in a healthy individual wherein anormal platelet count ranges from 150,000 and 450,000 per mm³ (ormicrolitre) (150-450×10̂9/L). These limits, however, are determined bythe 2.5th lower and upper percentile, and a deviation does not necessaryimply any form of disease nor alleviate the need for treatment as hereinproposed. Administering the herein disclosed compounds orcombinations/compositions comprising the same will have the effect ofpreserving the platelet count in an individual in need hereof. Asfollows here from, the individual will thus be receiving animmunostimulating treatment. The immunostimulating treatment will be byindirect immunostimulation as it regards the number/function of theplatelets.

It is thus an object of the present invention that the herein disclosedcompounds, combinations hereof and compositions comprising thesecompounds are for use in the treatment of immunodeficiency and/orthrombocytopenia and/or critical illness and/or for use as (indirect)immunostimulating compounds/compositions. These compounds andcompositions are to the preservation of platelet counts within normallevels in subjects in need there of, such subjects include subjectssuffering from immunodeficiency and/or in need of immuno stimulationand/or subjects suffering from critical illness.

It follows that the compound and compositions of the present inventionmay be used for immunotherapy, especially activating immunotherapy whichis defined as treatment of a condition or a disease by inducing and/orenhancing an immune response.

Therefore an object of the present invention relates to the use of thepharmaceutical compositions herein disclosed for the preservation ofplatelet number and/or function. The recipient of the treatment may be acritically ill patient requiring medical intervention to achievehomeostasis.

In a further aspect the present invention relates to a method ofdiagnosing critically ill patients at increased risk of development oforgan failure, including MOF, such as TAMOF, employing a viscoelasticalcitrated whole blood assay, such as TEG analysis, upon arrival to theICU, for those patients presenting either with a hypocoagulable TEG,defined as a cut-off value wherein (when using Kaolin activated citratedwhole blood) a R higher than 8 minutes, such as 8.5 minutes or higher,and/or MA lower than 51 mm, such as lower than 50 mm and/or Angle lowerthan 55°, such as lower than 52° or a hypercoagulable TEG defined as Rlower than 4.0 minutes, such as lower than 3.0 minutes, angle higherthan 80°, and MA higher than 69 mm, such as higher than 72 mm.

DEFINITIONS

The term “antiaggregatory” is intended to mean a lower than normalability of the platelets to interact in the clot building processsecondary to administration of compounds and/or variants that inhibitthe platelets ability to aggregate [Kawasaki et al 2007, Fries et al.2006, Velik-Salchner et al. 2007, Bassus et al. 2006, Tomokiyo et al.2003].

The term “antithrombotic” is also intended to mean a lower than normalability of the platelets to interact in the clot building processsecondary to administration of compounds and/or variants that inhibitand/or decreases the platelets ability to aggregate and inhibit theplatelets ability to form clots (thrombus formation).

The terms “antiaggregatory” and “antithrombotic” is used interchangeablyand refers to the effect of compound(s) that reduces the plateletsability to interact in the clot building process and hence form thrombi.

The term “modulating/preserving endothelial integrity” is intended tomean pharmacological treatment aiming at maintaining the endothelium ina quiescent inactivated anti-coagulant state. Thus a “compound capableof modulating/preserving endothelial integrity” is intended to mean anycompound that may assist in maintaining/inducing the endothelium in aquiescent inactivated anti-coagulant state.

The term “fibrinolytic activity” or fibrinolysis is intended to meanprocess wherein a fibrin clot, the product of coagulation, is brokendown.

The term “augmenting fibrinolytic activity” is intended to meanpharmacological treatment aiming at augmenting the break down of fibrinclots.

The term “hypocoagulability” used herein will reflect a slowerinitiation phase (increased R), and/or reduced thrombin burst (decreasedAngle) and/or reduced clot strength (reduced MA) as evaluated by TEG ascompared to the normal reference.

The term “hypercoagulability” used herein will reflect an increasedcoagulation activity in the initiation phase (decreased R), and/orincreased thrombin burst (increased Angle) and/or increased clotstrength (increased MA) as evaluated by TEG as compared to the normalreference.

The term “homeostasis” refers to the body's ability to regulatephysiologically its inner environment to ensure its stability. Aninability to maintain homeostasis may lead to death or a disease.

The term “Organ Failure” is altered organ function in an acutely illpatient requiring medical intervention to achieve homeostasis; organfailure includes as used herein Multi Organ Failure “MOF” andThrombocytopenia Associated Multi Organ Failure “TAMOF”.

The term “MOF” (Multi Organ Failure) is altered organ function in anacutely ill patient requiring medical intervention to achievehomeostasis; MOF includes as used herein TAMOF. MOF is also known asMultiple organ dysfunction syndrome (MODS).

The term “TAMOF” (Thrombocytopenia Associated Multi Organ Failure) usedherein will reflect any condition affecting critically ill patientsrelated to development of multiorgan failure secondary to a pathologicalconsumption of platelets resulting in thrombus formation in themicrocirculation either due to thrombotic microangiopathic disease orsecondary to disseminated intravascular coagulation or any othercondition associated with a decline in platelet count and/or function.

The term “TAID” (thrombocytopenia associated immunodeficiency) usedherein refers to a defective immunologic competence and/or dysregulatedinflammatory response resulting in increased risk of acquiring aninfection, dissemination of an established infection and/or excessivedysregulated inflammation with accompanying increased morbidity andmortality.

The term “critically ill”, herein also acutely ill, is meant to includeany condition rendering the patient in need for intensive care therapy.Intensive care therapy may include but is not limited to induction ofhomeostasis, ventilation (eg. mechanical ventilation), haemodialysis,vasopressor support, fluid support, parenteral nutrition, administrationof red blood cell concentrates, fresh frozen plasma, plateletconcentrates, whole blood, systemic antibiotic and/or antiviral and/orantifungal and/or antiprotozoic therapy, granulocyte infusion, T cellinfusion, stem cell infusion, anticoagulant therapy including but notlimited to administration of activated protein C and/or antithrombinand/or TFPI and/or heparins, including low molecular weight heparins,and/or thrombin inhibitors, administration of corticosteroids, tightglycemic control.

A “subject” includes humans and other mammals, and thus the methods areapplicable to both human therapy and veterinary applications, inparticular to human therapy. The term “mammal” includes humans,non-human primates (e.g. baboons, orangutans, monkeys), mice, pigs,cows, goats, cats, dogs, rabbits, rats, guinea pigs, hamsters, horse,monkeys, sheep or other non-human mammal.

“Treatment”, as used in this application, is intended to include bothprevention of an expected development or treatment of an establishedorgan failure, including MOF. Four classes of compounds are envisaged asbeneficial for this purpose:

“Reperfusion injury” as used herein refers to damage to tissue causedwhen blood supply returns to the tissue after a period of ischemia. Theabsence of oxygen and nutrients from blood creates a condition in whichthe restoration of circulation results in inflammation and oxidativedamage through the induction of oxidative stress rather than restorationof normal function.

The term “systemic inflammation” is altered organ function in an acutelyill patient due to the nonspecific conserved response of the body(vasculature, immune system, tissues) to infections, non-infectiousantigens, trauma, burn, organ/tissue destruction/degeneration/damage,ischemia, haemorrhage, intoxication, and/or malignancy.

“Sepsis” as used herein is intended to refer to whole-body inflammatorystate (called a systemic inflammatory response syndrome or SIRS) and thepresence of a known or suspected infection. Severe sepsis occurs whensepsis leads to organ dysfunction, low blood pressure (hypotension), orinsufficient blood flow (hypoperfusion) to one or more organs (causing,for example, lactic acidosis, decreased urine production, or alteredmental status). Sepsis can lead to septic shock, multiple organdysfunction syndrome/multiple organ failure, and death. Organdysfunction results from sepsis-induced hypotension (<90 mmHg or areduction of >40 mmHg from baseline) and diffuse intravascularcoagulation, among other things.

Examples of end-organ dysfunction include the following:

-   -   Lungs        -   acute lung injury (ALI) (PaO₂/FiO₂<300) or acute respiratory            distress syndrome (ARDS) (Pa02/Fi02<200)    -   Brain        -   encephalopathy            -   symptoms:                -   agitation                -   confusion                -   coma            -   etiologies:                -   ischemia                -   hemorrhage                -   microthrombi                -   microabscesses                -   multifocal necrotizing leukoencephalopathy    -   Liver        -   disruption of protein synthetic function: manifests acutely            as progressive coagulopathy due to inability to synthesize            clotting factors        -   disruption of metabolic functions: manifests as cessation of            bilirubin metabolism, resulting in elevated unconjugated            serum bilirubin levels (indirect bilirubin)    -   Kidney        -   oliguria and anuria        -   electrolyte abnormalities        -   volume overload    -   Heart        -   systolic and diastolic heart failure, likely due to            cytokines that depress myocyte function        -   cellular damage, manifest as a troponin leak (although not            necessarily ischemic in nature)

“SIRS” or systemic inflammatory response syndrome as used herein isintended to mean systemic inflammation in response to an insult withoutconfirmed infectious process. When an infection is suspected or proven(by culture, stain, or polymerase chain reaction (PCR)), together withSIRS, this is per definition sepsis. Specific evidence for infectionincludes WBCs in normally sterile fluid (such as urine or cerebrospinalfluid (CSF), evidence of a perforated viscus (free air on abdominalx-ray or CT scan, signs of acute peritonitis), abnormal chest x-ray(CXR) consistent with pneumonia (with focal opacification), orpetechiae, purpura, or purpura fulminans

“Trauma” as used herein is intended to mean any body wound or shockproduced by sudden physical injury, as from accident, injury, or impact.

EMBODIMENTS

As described herein above, a main aspect of the invention relates tocompounds for treatment that protects the endothelium, preventpathologic thrombus formation in the microcirculation and preserveplatelet number and function and thus may be related to minimizing orpreventing development of organ failure, including multiple organfailure (MOF), and, hence, death in critically ill patients byadministration of compound(s) limiting the platelets ability toaggregate and form clots and/or by agents modulating/preservingendothelial integrity and/or by agent(s) increasing the rate of thrombuslysis, and pharmaceutical compositions comprising one or more of any ofthe compounds mentioned.

Said compounds are preferably antithrombotic compounds and are morepreferably selected from one or more of the groups described hereinbelow.

Antithrombotic Compounds

-   -   1. Platelet inhibitors    -   2. Agents modulating/preserving endothelial integrity    -   3. Pro-fibrinolytic compounds    -   4. Inhibitors against TAFIa

Antithrombotic compounds belonging to the four different groups aredisclosed below. It is envisaged that more than one compound from eachof the four classes may be administered to a person in need thereof forthe prevention or treatment of organ failure, including MOF, inparticular TAMOF in critically ill patients and patients with systemicinflammation. In a particular embodiment at least two compounds from atleast two of the different classes listed above or one compound from oneof the different classes listed above are administered to a person inneed thereof for the prevention or treatment of critical illness,systemic inflammation, organ failure, including MOF, in particularTAMOF.

In the following, names of compounds of relevance for the presentinvention are listed. Trade names covering any of the herein mentionedcompounds are also of relevance for the present invention.

Platelet Inhibitors

Platelet inhibitors are compounds that interfere with plateletactivation (including adhesion, secretion), aggregation and ultimateplatelet-fibrin clot formation. Consequently, platelet activationincluding secretion of alpha, dense, lysosomal and other granules arereduced or inhibited. Also, exposure of negatively chargedphosphatidylserine on the platelet surface is reduced or inhibited.Furthermore, activation of the GPIIb/IIIa receptor, being the finalcommon pathway for activation by the thromboxane receptor, ADP receptorand PAR receptors is prevented or limited. In addition, exposure severalplatelet receptors and/or molecules are reduced or inhibited.

Any agent that reversibly or irreversibly reduces and more preferablyinhibits platelet activation/aggregation by blocking sites on theplatelet surface or capable of intracellular inhibition can be used asthe platelet inhibitor in the present invention.

Platelet inhibitors according to present invention may include any agentthat is intended to be used as an antithrombotic or antiaggregatoryagent. Any agent that reversibly or irreversibly reduces and morepreferably inhibits platelet activation/aggregation by blocking sites onthe platelet surface or capable of intracellular inhibition of pathwaysthat mediates platelet activation can be used as the platelet inhibitorin the present invention.

A non-exhaustive list of examples of platelet inhibitors for theprevention or treatment of organ failure including MOF and TAMOF incritically ill patients and/or patients with systemic inflammationencompass the following:

-   -   1. Compounds inhibiting the platelet GPIIb/IIIa receptor such        as: abciximab, eptifibatide, tirofiban, orbofiban, xemilofiban,        lamifiban, XJ757, DUP728, XR299, linear or novel cyclic RGD        peptide anlogs, cyclic petides, peptidomimetics inhibiting this        receptor and the like, and mixtures hereof and other compounds.    -    In a particular embodiment the compound inhibiting the platelet        GPIIb/IIIa receptor is administered together with a prostacyclin        or a prostacyclin analog, see below.    -   2. Compounds inhibiting the platelet ADP receptor (P2Y12) such        as: AR-C69931 MX, Ticlopidine, Clopidogrel, Prasugrel, AZD6140,        cangrelor, ticagrelor and other compounds inhibiting this        receptor.    -    In a particular embodiment the compound inhibiting the platelet        ADP receptor (P2Y12) is administered together with a        prostacyclin or a prostacyclin analog, see below.    -   3. Compounds inhibiting the platelet P2Y1 receptor such as:        MRS2500, MRS2298, MRS2496, A2P5P, A3P5P, ATP, 2-MeSATP, and        2-CIATP.    -    In a particular embodiment the compound inhibiting the platelet        receptor (P2Y1) is administered together with a prostacyclin or        a prostacyclin analog, see below.    -   4. Compounds inhibiting the platelet COX1 and/or COX2 pathways        such as        -   a. COX inhibitors which have the ability to inhibit as well            COX1 as COX2, such as            -   i. Salicylates selected from the group consisting of                Acetylsalicylic acid (Aspirin), Amoxiprin,                Benorylate/Benorilate, Choline magnesium salicylate,                Diflunisal, Ethenzamide, Faislamine, Methyl salicylate,                Magnesium salicylate, Salicyl salicylate and                Salicylamide;            -   ii. Arylalkanoic acids selected from the group                consisting of Diclofenac, Aceclofenac, Acemethacin,                Alclofenac, Bromfenac, Etodolac, Indomethacin,                Nabumetone, Oxametacin, Proglumetacin, Sulindac and                Tolmetin;            -   iii. 2-Arylpropionic acids (profens) selected from the                group consisting of Ibuprofen, Alminoprofen,                Benoxaprofen, Carprofen, Dexibuprofen, Dexketoprofen,                Fenbufen, Fenoprofen, Flunoxaprofen, Flurbiprofen,                Ibuproxam, Indoprofen, Ketoprofen, Ketorolac,                Loxoprofen, Naproxen, Oxaprozin, Pirprofen, Suprofen and                Tiaprofenic acid;            -   iv. N-Arylanthranilic acids (fenamic acids) selected                from the group consisting of Mefenamic acid, Flufenamic                acid, Meclofenamic acid and Tolfenamic acid;            -   v. Pyrazolidine derivatives selected from the group                consisting of Phenylbutazone, Ampyrone, Azapropazone,                Clofezone, Kebuzone, Metamizole, Mofebutazone,                Oxyphenbutazone, Phenazone and Sulfinpyrazone;            -   vi. Oxicams selected from the group consisting of                Piroxicam, Droxicam, Lornoxicam, Meloxicam and                Tenoxicam;    -   b. COX inhibitors which are specific for inhibition of COX2 such        as Celecoxib, Etoricoxib, Lumiracoxib, Parecoxib, Rofecoxib,        Valdecoxib, Nimesulide, Licofelone and Omega-3 fatty acids.    -    In a particular embodiment the compound inhibiting COX is        administered together with a prostacyclin or a prostacyclin        analog, see below    -   5. Compounds inhibiting thromboxane-synthase (TX-synthase) such        as flavonoids and thromboxane receptor (TP)-antagonists, such as        SQ29548, Bay u 3405, or BM 13.177.    -    In a particular embodiment the compound inhibiting        thromboxane-synthase (TX-synthase) and/or thromboxane receptor        (TP)-antagonists is administered together with a prostacyclin or        a prostacyclin analog, see below.    -   6. Compounds inhibiting adenosine uptake in the platelets such        as dipyramidol, Persantin, Asasantin, Aggrenox and other        compounds with a similar mode of action.    -    In a particular embodiment the compound inhibiting adenosine        uptake in the platelets is administered together with a        prostacyclin or a prostacyclin analog, see below.    -   7. Compounds inhibiting the platelet GPIb receptor, such as mAB        Ib-23, mAB 6B4, R9alpha557 peptide, aurintricarboxylic acid        (ATA), crotalin, agkistin, peptide        (Trp-Ile-Arg-Arg-Pro-Phe-Phe-Pro-Phe) from alpha B-crystallin.    -    In a particular embodiment the compound inhibiting the platelet        GPIb receptor is administered together with a prostacyclin or a        prostacyclin analog, see below.    -   8. Compounds inhibiting the platelet GPVI receptor, such as        EXP3179, triplatin-1 and -2, JAQ1, mAB 10B12, mAB 1C3, mAb 12G1.    -    In a particular embodiment the compound inhibiting the platelet        GPVI receptor is administered together with a prostacyclin or a        prostacyclin analog, see below.    -   9. Compounds inhibiting the PAR receptors such as thrombin        inhibitors, heterocycle-based peptide-miimetic antagonists of        PAR-1, RWJ-56110 and RWJ-58259, SCH 79797, SCH 203099, and PAR4        antagonists such as trans-cinnamoyl-YPGKF-amide (tc-Y-NH(2)) and        palmitoyl-SGRRYGHALR-amide (P4pa110), PAR-2 antagonist        ENMD-1068, PAR2 monoclonal antibody SAM-11.    -    In a particular embodiment the compound inhibiting the PAR        receptors is administered together with a prostacyclin or a        prostacyclin analog, see below.    -   10. Phosphodiesterase inhibitor PDE3 such as Cilostazol with        therapeutic focus on increasing cAMP. An increase in cAMP        results in an increase in protein kinase A (PKA), which is        directly related with an inhibition in platelet aggregation.    -    In a particular embodiment the Phosphodiesterase inhibitor is        administered together with a prostacyclin or a prostacyclin        analog, see below.    -   11. Nitroaspirin (NCX4016) an aspirin that can release NO.    -    In a particular embodiment nitroaspirin is administered        together with a prostacyclin or a prostacyclin analog, see below    -   12. A compound of albumin conjugated with polyethylene glycol        (PEG).    -    In a particular embodiment the albumin conjugated with PEG        inhibitor is administered together with a prostacyclin or a        prostacyclin analog, see below.    -   13. A compound of haemoglobin conjugated with polyethylene        glycol, a compound that besides its platelet inhibitory function        also improves oxygenation of the microvasculature, such as but        not exclusively MP40X (Hemospan, polyethylene glycol-hemoglobin        complexes)    -    In a particular embodiment the hemoglobin conjugated to PEG is        administered together with a prostacyclin or a prostacyclin        analog, see below.    -   14. Antibodies and/or inhibitors of C-type lectin-like receptor        2 (CLEC-2) [May et al 2009] In a particular embodiment the        antibodies/inhibitors of CLEC-2 is administered together with a        prostacyclin or a prostacyclin analog, see below.    -   15. High-energy glycolitic metabolites like        fructose-1,6-bisphosphate (FBP) [de Oliveira et al]    -    In a particular embodiment the FBP is administered together        with a prostacyclin or a prostacyclin analog, see below.

In a preferred embodiment the platelet inhibitor has a half time of lessthan 3 hours (such as eptifibatide), preferably less than 2.5 hours(such as tirofiban), more preferably less than 1 hour (such asabciximab). In a preferred embodiment a compound inhibiting the plateletGPIIb/IIIa receptor is administered. Eptifibatide is an example of amost preferred compound.

In another preferred embodiment the platelet inhibitor has a half timeof less than 12 hours (such as Ticlopidine), preferably less than 8hours (such as Clopidogrel), more preferably about 3-5 min (such ascangrelor). Another preference is in the reversibility of the ADPreceptor inhibition: Ticagrelor is an example of a compound that blocksthe receptor in a reversible manner and Ticagrelor is for this reasonpreferable. Thus in an equally preferred embodiment a compoundinhibiting the platelet ADP receptor (P2Y12) is administered.

In regards to the half lives/half times of the herein mentionedcompounds: the half time depends on the administration form and/or thedosage. In general, intravenous administration is preferred.

Agents Modulating/Preserving Endothelial Integrity

The endothelium maintains under physiological conditions a normalvascular function by regulating the balance between vasodilator andvasoconstrictor mediators and by regulating the expression of adhesionreceptors. Endothelial modulators encompass any agent that affects theendothelium to either maintain or develop into a non-activated quiescentstate, which optimally preserves and ensures vascular integrity. In astate with vascular integrity, the endothelium exerts anti-inflammatoryand anti-thrombotic properties down-regulating and counteractingplatelet activation through the generation of PGI2 (prostaglandin 12,prostacyclin) and through the production of ADPase, the lattercatalyzing the degradation of ADP. Endothelial cells can also preventthe activation of the coagulation cascade by expressing surfacemolecules with anticoagulant properties such as heparan sulfate,dermatan sulfate, tissue factor pathway inhibitor (TFPI), protein S (PS)and thrombomodulin (TM). Endothelial cells express plasminogen,tissue-type plasminogen activator (tPA), urokinase-type plasminogenactivator (uPA), urokinase-type plasminogen activator receptor (uPAR) aswell as membrane-associated plasminogen activator binding sites, thusfavouring the generation of plasmin, and they express endothelialprotein C receptor (EPCR), which enhances the anticoagulant activity.

The endothelial modulators may be selected from any of the classes ofcompounds (1-11) described below:

-   -   1. Compounds such as PGI2, PGX, prostacyclin (Epoprostenol) or        variants thereof, such as beraprost sodium, epoprostenol sodium,        iloprost, iloprost in combination with bosentan, iloprost in        combination with sildenafil citrate, treprostinil, pegylated        treprostinil, treprostinil diethanolamine and treprostinil        sodium. Further compounds are        2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfony-1)acetamide,        {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic        acid, 8-[1,4,5-triphenyl-1H-imidazol-2-yl-oxy]octanoic acid,        isocarbacyclin, cicaprost,        [4-[2-(1,1-Diphenylethylsulfanyl)-ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxy]-acetic        acid N-Methyl-d-glucamine,        7,8-dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-methiminoxy)-ethyl)-α-naphthyloxy-acetic        acid, (5-(2-diphenylmethyl        aminocarboxy)-ethyl)-a-naphthyloxyaceticacid,        2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid,        [3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid,        bosentan, 17[alpha],20-dimethyl-[DELTA]6,6a-6a-carba PGI1, and        15-deoxy-16 [alpha]-hydro xy-16        [beta],20-dimethyl-[DELTA]6,6a-6a-carba PGI1,        pentoxifylline(1-{5-oxohexyl}-3,7-dimethylxanthine).    -    Trade names for prostacyclins include, but are not limited to:        flolan, remodulin, and ventavis.    -   2. A combination of prostacyclin or a prostacyclin analogue and        endothelin receptor antagonist may improve the safety profile of        prostacyclin therapy by reducing potential side effects of        prostacyclin such as jaw pain, headache and hypotension.    -   3. Compounds with modulating/preserving endothelial effects such        as nitric oxide (also Endothelium Derived Relaxing Factor)        produced by healthy endothelial cells induce vasodilatation and        favours an anti-adhesive and anti-inflammatory phenotype of the        endothelium through a rise in cytosolic cGMP [Cines et al 1998;        Zardi et al 2005].    -   4. CD39 and CD73 are vascular membrane-bound ecto-nucleotidases        expressed at the luminal surface of healthy endothelial cells.        They hydrolyze extracellular plasma ATP and ADP and thereby        inhibit nucleotide mediated platelet activation [Atkinson et al        2006; Colgan et al 2006]. In addition to platelet inhibition,        soluble CD39 and CD73 agonists inhibit endothelial cell        apoptosis and activation [Goepfert et al 2000] and prevent        hypoxia induced vascular leakage [Thompson et al 2004].    -   5. Compounds involved in redox control of endothelial functions        such as: L-Arginine and tetrahydrobiopterin, Antioxidants        (Ascorbate, Glutathione, α-tocopherol, ubiquinol-10, Probucol),        Iron chelators, and Polyphenols.    -   6. Clinical drugs involved in redox control of endothelial        functions such as: HMG-CoA reductase inhibitors (Fluvastatin,        Lovastatin, Pravastatin, Simvastatin), Angiotensin-receptor        antagonists and ACE inhibitors (Captopril, Zofenopril,        Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril,        Benazepril, Fosinopril, Casokinins, lactokinins), Peroxisome        proliferator-activated receptors (PPARs), NADPH oxidase,        Xanthine oxidase, PETN, Heparan sulfates (PI-88), heparan        sulfate mimetics, Activators of oxidized/heme-free sGC (BAY        58-2667), and Anti-PECAM/SOD.    -   7. Honokiol, a biphenyl neolignan isolated from Hou pu, the        cortex of Magnolia officinalis.    -   8. Compounds that directly modulate endothelial barrier function        through modulating effects on sphingosine-1-phosphate        (S1P)-receptors (eg.: FTY720, AA-R, AAL-S, KRP-203, AUY954,        CYM-5442, SEW2871, W146, W140, VPC44116, VPC23019, JTE-013)        [Marsolais et al 2009].    -   9. Antibodies and/or other molecules against/antagonizing        histones that through their inhibition diminishes        histone-mediated endothelial damage and/or microthrombi        formation and/or fibrin deposition [Xu et al 2009].    -   10. Compounds enhancing the natural anticoagulant pathways and        hence protecting the endothelium such as but not exclusively:        Protein C pathway (Activated protein C (APC, Drotrecogin alfa),        protein C, compounds that either mimics and/or protects from        degradation and/or enhances soluble thrombomodulin and/or EPCR        and/or protein S), Antithrombin III (ATIII) (or ATIII like        compounds and/or compounds that enhance ATIII function) and        tissue factor pathway inhibitor (TFPI) (or TFPI compounds and/or        compounds that enhance TFPI function).    -   11. Compounds that maintain and/or promote Gβγ function and/or        signalling following endothelial PAR activation to ensure        reannealing of adherens junctions opened following inflammatory        PAR mediated activation of Ga [Knezevic et al 2009]

Various other potential target sites to modulate the endothelialfunction, activation state and integrity are given in Table 3, below.

TABLE 3 Potential endothelial modulating target sites TargetsCompound 1. Inhibition of Rho-kinase Fasudil Y-27632 2. Inhibition ofPARP PJ-34 INO 1001 3-Aminobenzamide 3. Inhibition of PTPaseBis(malotalo) oxovanadium 4. Activation of Akt Demethylasterriquinone 5.Activation of PKA 8-Br-cAMP 6. Inhibition of caveolin Daidzein 7.estrogen-receptor (ER) agonist 17-beta-Estradiol 8. Activation of PPARalpha Fibrates PPAR gamma Thiazolidinediones PPAR delta GW 07242 9.Inhibition of CETP Torcetrapib CETi-1 vaccine 10. Activation oflipoprotein lipase NO-1886 11. Activation of S1P FTY720 12. Activationof transketolase Benfotiamine 13. Inhibition of GGT GGTI-298 14.Inhibition of epoxide hydrolase 1-Cyclohexyl-3-dodecylureaN,N′-Dicyclohexylurea N,N′-Adamantanyl-N′-dodecanoic urea 15. Activationof ACE 2 AVE 0991 16. Inhibition of JAK AG-490 WHI-P154

Prostacyclin, a metabolite of arachidonic acid, is a naturally occurringprostaglandin with potent vasodilatory activity and inhibitory activityof platelet aggregation, released by healthy endothelial cells.Prostacyclin performs its function through a paracrine signallingcascade that involves G protein-coupled receptors on nearby plateletsand endothelial cells. In the clinical setting, Epoprostenol(prostacyclin analogue) has 2 major pharmacological actions: (1) directvasodilation of pulmonary and systemic arterial vascular beds, and (2)inhibition of platelet aggregation. Epoprostenol is indicated for thelong-term intravenous treatment of primary pulmonary hypertension andpulmonary hypertension associated with the scleroderma spectrum ofdisease in NYHA Class III and Class IV patients who do not respondadequately to conventional therapy. The antiaggregatory effect ofprostacyclin analogs on platelets is mediated by the Gas protein-coupledreceptor (prostacyclin receptor, IP) that is activated upon prostacyclinanalog binding. This activation signals adenylyl cyclase to producecAMP, which in turn activates Protein Kinase A to decrease freeintracellular calcium concentrations. The rise in cAMP directly inhibitsplatelet activation (secretion and aggregation) and counteractsincreases in cytosolic calcium resulting from platelet activation byagonists such as thrombin, ADP, TXA2, PAF, collagen and 5-HT [Bihari etal, 1988; Schereen et al, 1997; Xing et al 2008].

The modulating/preserving effect on endothelial integrity is mediated bybinding of prostacyclin analog to endothelial prostacyclin receptorswith ultimate rise in cytosolic cAMP and Protein Kinase A activation.This leads to smooth muscle relaxation and vasodilatation with improvedmicrovascular perfusion and “cytoprotection” through stabilization oflysozomal and cell membranes with reduced inflammation. It also favoursan anti-coagulant, anti-adhesive, anti-apoptotic and anti-inflammatoryphenotype of the endothelium, less likely to support coagulation,leukocyte adhesion/migration and inflammation [Zardi et al 2005; Zardiet al 2007].

In a preferred embodiment the compound capable of modulating/preservingthe endothelial integrity has a half time of less than 4 hours (such asTreprostinil), preferably less than 1 hours (such as Beraprost (35-40min)), more preferably less than ½ hour (such as Iloprost (20-30 min)),preferably less than 5 min (such as Epoprostenol (0.5-3 min))

Pro-fibrinolytics

Also denoted compounds capable of augmenting the fibrinolytic activityin whole blood. This group includes compounds such as (t-PA, u-PA) or(rt-PA, ru-PA) such as: Actilyse, Metalyse, Rapilysin, Streptase,Urokinase and other compounds containing t-PA and/or rt-PA, uPA, r-uPA.

TAFIa Inhibitors

Also denoted compounds that inhibit thrombin-activatable fibrinolysisinhibitor (TAFIa). Compounds included in this class are for exampleCPU-I, AZD9684, MERGETPA, Compound 21 (UK-396,082) and other compoundswith a similar effect.

Combinations

Administration of combinations of the compounds discussed herein is alsoenvisaged by the present invention as discussed above.

The invention relates to a pharmaceutical composition comprising one ormore one or more compounds selected from the group consisting ofplatelet inhibitors, compounds capable of modulating/preserving theendothelial integrity, compounds capable of augmenting the fibrinolyticactivity, or TAFIa inhibitors.

Thus the invention relates to any combination of any of the classes ofcompounds mentioned above (platelet inhibitors, endothelial modulators,pro-fibrinolytics, TAFIa-inhibitors), such as one compound, such as atleast two compounds, such as at least three compounds. When using morethan one compound the compounds may be selected from the same class ofcompounds, or more preferably the at least two compounds may be selectedfrom different classes of compounds.

Accordingly, in one embodiment one compound is selected from a compoundcapable of modulating/preserving the endothelium (endothelial modulator)and the at least one other compound is selected from a compound capableof inhibiting the platelets (platelet inhibitor), a compound capable ofincreasing fibrinolysis either directly (pro-fibrinolytics) orindirectly (TAFIa-inhibitors).

In another embodiment one compound is selected from a compound capableof inhibiting the platelets (platelet inhibitor) and the at least oneother compound is selected from a compound capable ofmodulating/preserving the endothelium or increasing fibrinolysisdirectly (pro-fibrinolytics) or indirectly (TAFIa-inhibitors).

In a third embodiment one compound is selected from a compound capableof directly enhancing fibrinolysis (pro-fibrinolytics) and the at leastone other compound is a TAFIa-inhibitor.

Accordingly, combination treatment may include administration of anycombination of one or more anti-thrombotic compounds, such as one ormore of the following: platelet inhibitors including but not limited toGPIIb/IIIa inhibitors, ADP receptor inhibitors, P2Y1 inhibitors, COX1and COX2 inhibitors, TX-synthase inhibitors, adenosine uptakeinhibitors, GPIb inhibitors, GPVI inhibitors, PAR receptor inhibitors,phosphodiesterase inhibitors, nitroaspirin, albumin conjugated withpolyethylene glycol, MP4OX, anti-CLEC-2 antibodies, FBP or similarcompounds and/or endothelial modulators including but not limited toPGI2/prostacyclin analogues and variants hereof,prostacyclin/prostacyclin analogue combined with endothelin receptorantagonists, NO, CD39, CD73, compounds involved in redox control,clinical drugs involved in redox control (HMG-CoA reductase inhibitors),Honokiol, compounds modulating S1P-receptors, antibodies and/or othermolecules against/antagonizing histones, compounds enhancing/modulatingthe natural anticoagulant pathways such as the protein C pathwayincluding but not limited to APC, PC, PS, sTM, sEPCR), ATIII pathway(ATIII), TFPI pathway (TFPI), Gβγ stimulators and/or anypro-fibrinolytics such as t-PA, u-PA, rt-PA, ru-PA (Actilyse, Metalyse,Rapilysin, Streptase, Urokinase and other compounds containing t-PAand/or rt-PA, uPA, r-uPA and any TAFIa-inhibitors including but notlimited to CPU-I, AZD9684, MERGETPA, Compound 21 (UK-396,082) and othercompounds with a similar effect.

Thus, in preferred embodiments platelet inhibitor is selected from thegroup consisting of abciximab, eptifibatide, tirofiban, orbofiban,xemilofiban, lamifiban, XJ757, DUP728 and XR299 and the compound capableof modulating/preserving the endothelial integrity is selected from thegroup consisting of PGI2, PGX, nitrogen oxide, CD39, CD73 andprostacyclin or variants thereof, such as beraprost sodium, epoprostenolsodium, iloprost, iloprost in combination with bosentan, iloprost incombination with sildenafil citrate, treprostinil, pegylatedtreprostinil, treprostinil diethanolamine and treprostinil sodium,2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfony-1)acetamide,{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid,8-[1,4,5-triphenyl-1H-imidazol-2-yl-oxy]octanoic acid, isocarbacyclin,cicaprost,[4-[2-(1,1-Diphenylethylsulfanyl)-ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxy]-aceticacid N-Methyl-d-glucamine,7,8-dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-methiminoxy)-ethyl)-a-naphthyloxy-aceticacid, (5-(2-diphenylmethyl aminocarboxy)-ethyl)-a-naphthyloxyaceticacid,2-[3-[2-(4,5-diphenyl-2-oxazolyl]ethyl]phenoxy]acetic acid,[3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid,bosentan, 17 [alpha],20-dimethyl-[DELTA]6,6a-6a-carba PGI1, 15-deoxy-16[alpha]-hydroxy-16 [beta],20-dimethyl-[DELTA]6,6a-6a-carba PGI1 andpentoxifylline(1-{5-oxohexyl}-3,7-dimethylxanthine).

In another equally preferred embodiment the platelet inhibitor isselected from the group consisting of AR-C69931 MX, Ticlopidine,Clopidogrel, Prasugrel, AZD6140 and cangrelor, ticagrelor and thecompound capable of modulating/preserving the endothelial integrity isselected from the group consisting of PGI2, PGX, nitrogen oxide, CD39,CD73 and prostacyclin or variants thereof, such as beraprost sodium,epoprostenol sodium, iloprost, iloprost in combination with bosentan,iloprost in combination with sildenafil citrate, treprostinil, pegylatedtreprostinil, treprostinil diethanolamine and treprostinil sodium,2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfony-1)acetamide,{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid,8-[1,4,5-triphenyl-1H-imidazol-2-yl-oxy]octanoic acid, isocarbacyclin,cicaprost,[4-[2-(1,1-Diphenylethylsulfanyl)-ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxy]-aceticacid N-Methyl-d-glucamine,7,8-dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-methiminoxy)-ethyl)-a-naphthyloxy-aceticacid, (5-(2-diphenylmethyl aminocarboxy)-ethyl)-a-naphthyloxyaceticacid, 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid,[3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid,bosentan, 17 [alpha],20-dimethyl-[DELTA]6,6a-6a-carba PGI1, 15-deoxy-16[alpha]-hydroxy-16 [beta],20-dimethyl4DELTA]6,6a-6a-carba PGI1 andpentoxifylline(1-{5-oxohexyl}-3,7-dimethylxanthine).

In other preferred embodiments the platelet inhibitor is capable ofinhibiting the GPIIb/IIIa receptor and has a half time of less than 3hours (such as eptifibatide), preferably less than 2.5 hours (such astirofiban), more preferably less than 1 hour (such as abciximab) and thecompound capable of modulating/preserving the endothelial integrity ahalf time of less than has a half time of less than 4 hours (such asTreprostinil), preferably less than 1 hours (such as Beraprost (35-40min)), more preferably less than ½ hour (such as Iloprost (20-30 min)),preferably less than 5 min (such as Epoprostenol (0.5-3 min)).

In other preferred embodiments the platelet inhibitor is capable ofinhibiting platelet ADP receptor P2Y12 and has a half time of 12 hours(such as Ticlopidine), preferably less than 8 hours (such asClopidogrel), more preferably about 3-5 min (such as cangrelor) and thecompound capable of modulating/preserving the endothelial integrity ahalf time of less than has a half time of less than 4 hours (such asTreprostinil), preferably less than 1 hours (such as Beraprost (35-40min)), more preferably less than ½ hour (such as Iloprost (20-30 min)),preferably less than 5 min (such as Epoprostenol (0.5-3 min))

Furthermore, the treatment may include administration of one or more ofthe antithrombotic compounds mentioned above in combination withtherapies including but not limited to plasma exchange or plasmainfusion, and/or anticoagulation with heparins (such as UFH, LMWH),and/or antithrombin and/or activated protein C and/or TFPI and/orcoumadins and/or direct or indirect thrombin inhibitors and/or direct orindirect factor Xa inhibitors.

In particular a combination of platelet inhibitors and compound capableof modulating/preserving endothelial integrity is envisaged by thepresent invention, such as a combination of a GPIIb/IIIa plateletinhibitor and a prostacyclin, optionally further combined with othercompounds. A preferred combination is GPIIb/IIIa platelet inhibitor anda prostacyclin further combined with endothelin receptor antagonists.

Furthermore, the term “treatment” also includes administration of afibrinolysis activator, such as tissue plasminogen activator (tPA),urokinase plasminogen activator (uPA) or variants hereof alone or in anycombination of therapies including but not limited to antithromboticsand/or endothelial modulators (such as prostacyclin, NO) and/or plasmaexchange, plasma infusion, and/or anticoagulation with heparins (such asUFH, LMWH), and/or antithrombin and/or activated protein C and/or TFPIand/or coumadins and/or direct or indirect thrombin inhibitors and/ordirect or indirect factor Xa inhibitors).

The compounds to be applied in the method of the present invention maybe administered with at least one other compound. The compounds may beadministered simultaneously, either as separate formulations or combinedin a unit dosage form, or administered sequentially.

Dosages

As used herein, “dose” shall mean any concentration of the agentsadministered to the patient resulting in inhibition of theaggregating/clot forming properties of the platelets and/or maintainingthe endothelium in a quiescent state and/or a reduced resistance of thethrombus to fibrinolysis and/or preserving the platelet count and/orfunction. A dose sufficient to produce the desired effect in relation tothe conditions for which it is administered shall be described as the“effective dose” or “effective amount”.

As will be understood by the person skilled in the art, amountseffective for this purpose will depend on the number and functionalityof circulating platelets and endothelial cells in the patient and thenumber of receptors on the respective platelets and endothelial cells.

The dosage requirements will vary with the particular drug compositionemployed, the route of administration and the particular subject beingtreated. Ideally, a patient to be treated by the present method willreceive a pharmaceutically effective amount of the compound in themaximum tolerated dose, generally no higher than that required beforedrug resistance develops.

Administration of the compounds and/or compositions of the presentinvention are to be given to a subject resulting in a systemicconcentration of the compounds. Methods of administration includeenteral, such as oral, sublingual, gastric or rectal and/orparenterally, that is by intravenous, intraarterial, intramuscular,subcutaneous, intranasal, intrapulmonary, intrarectal, intravaginal orintraperitoneal administration. The subcutaneous and intravenous formsof parenteral administration are generally preferred. Appropriate dosageforms for such administration may be prepared by conventionaltechniques. The compounds may also be administered by inhalation that isby intranasal and oral inhalation administration. Appropriate dosageforms for such administration, such as an aerosol formulation or ametered dose inhaler, may be prepared by conventional techniques.

The compounds according to the invention may be administered with atleast one other compound. The compounds may be administeredsimultaneously, either as separate formulations or combined in a unitdosage form, or administered sequentially.

Normally the dose should be capable of preventing or lessening theseverity or spread of the condition or indication being treated. Theexact dose will depend on the circumstances, such as the condition beingtreated, the administration schedule, whether the compounds areadministered alone or in conjunction with another therapeutic agent, theplasma half-life of the compounds and the general health of the subject.

The compounds disclosed herein are generally well known to a personskilled in the art and the appropriate dosages for their use aredisclosed in pharmacopeias, pharmaceutical handbooks, and patientinformation leaflets. Thus the compounds of the present invention may beadministered n the dosages recommended by the manufacturers or as areknown to be efficient to those skilled in the art, i.e. medicalpractitioners.

As will be understood by the person skilled in the art, amountseffective for this purpose will depend on the severity of the disease orinjury as well as the weight and general state of the subject. The doseis preferably given by the parenteral administration route, notably theintravenous, intraarterial, intramuscular and/or the subcutaneous,sublingual, trans-mucosal, intrapulmonal and intra-alveolar route.

The dosages given in the following is contemplated to be in the sameorder of magnitude irrespective of the parenteral administration route.

For all methods of use disclosed herein for the compounds, the dailyparenteral dosage regimen about 0.001 to about 80 mg/kg of total bodyweight. The daily oral dosage regimen will preferably be from about 0.01to about 80 mg/kg of total body weight. The daily topical dosage regimenwill preferably be from 0.1 mg to 150 mg, administered one to four,preferably two or three times daily. The daily inhalation dosage regimenwill preferably be from about 0.01 mg/kg to about 1 mg/kg per day. Itwill also be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound or apharmaceutically acceptable salt thereof will be determined by thenature and extent of the condition being treated, the form, route andsite of administration, and the particular patient being treated, andthat such optimums can be determined by conventional techniques. It willalso be appreciated by one of skill in the art that the optimal courseof treatment, i.e., the number of doses of a compound or apharmaceutically acceptable salt thereof given per day for a definednumber of days, can be ascertained by those skilled in the art usingconventional course of treatment determination tests.

The term “unit dosage form” as used herein refers to physically discreteunits suitable as unitary dosages for human and animal subjects, eachunit containing a predetermined quantity of a compound, alone or incombination with other agents, calculated in an amount sufficient toproduce the desired effect in association with a pharmaceuticallyacceptable diluent, carrier, or vehicle. The specifications for the unitdosage forms of the present invention depend on the particular compoundor compounds employed and the effect to be achieved, as well as thepharmacodynamics associated with each compound in the host

It is an object of the present invention that the compounds and/orcompositions herein disclosed are administered systemically. It is alsoan object of the present invention that the compounds are administeredparenterally, preferably intravenously and/or intrarterially.

Pharmaceutical Compositions of the Invention and its Use

The present invention also relates to a pharmaceutical compositioncomprising any combination of any of the compounds mentioned above(platelet inhibitors, endothelial modulators, pro-fibrinolytics,TAFIa-inhibitors), such as one compound, such as at least two compounds,such as at least three compounds and one or more pharmaceuticallyacceptable carriers or excipients. Such pharmaceutically acceptablecarrier or excipient as well as suitable pharmaceutical formulationmethods are well known in the art (see for example Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.(1990). In a preferred embodiment the platelet inhibiting/endothelialprotecting variants are prepared in a parenteral composition. Suchmethods for preparing parenterally administrable compositions will alsobe known or apparent to those skilled in the art and are described inmore detail in, for example, Remington's Pharmaceutical Sciences, 18thed., Mack Publishing Company, Easton, Pa. (1990). As used herein, theterm “pharmaceutical acceptable” means carriers or excipients that doesnot cause any untoward effects in subjects to whom it is administered.

The compositions for parenteral administration comprise the plateletantiaggregatory agents of the invention in combination with, preferablydissolved in, a pharmaceutically acceptable carrier, preferably anaqueous carrier. A variety of aqueous carriers may be used, such aswater, buffered water, saline e.g. such as 0.7%, 0.8%, 0.9% or 1%,glycine such as 0.2%, 0.3%, 0.4% or 0.5% and the like. Normally, it isaimed that the composition has an osmotic pressure corresponding to a0.9% w/w sodium chloride solution in water. Moreover, as known by aperson skilled in the art, dependent on the specific administrationroute, pH may be adjusted within suitable ranges centred around pH 7.4.The compositions may be sterilised by conventional, well-knownsterilisation techniques. The resulting aqueous solutions may bepackaged for use or filtered under aseptic conditions and lyophilised,the lyophilised preparation being combined with a sterile aqueoussolution prior to administration.

The compositions may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions, such aspH adjusting and buffering agents, stabilizing agents, preservatives,non-ionic surfactants or detergents, antioxidants, tonicity adjustingagents and the like, for example, sodium acetate, sodium lactate, sodiumchloride, potassium chloride, calcium chloride, etc.

The main routes of drug delivery, in the treatment method areintravenous, oral, and topical, as will be described below. Otherdrug-administration methods, such as subcutaneous injection or viainhalation, which are effective to deliver the drug to a target site orto introduce the drug into the bloodstream, are also contemplated.

Compounds of the invention may be administered parenterally, that is byintravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. Appropriate dosage formsfor such administration may be prepared by conventional techniques. Thecompounds may also be administered by inhalation that is by intranasaland oral inhalation administration. Appropriate dosage forms for suchadministration, such as an aerosol formulation or a metered doseinhaler, may be prepared by conventional techniques.

The compounds are preferably administered intravenously and/orintraalveolar and it may be administered by continuous or pulsatileinfusion or as a bolus.

The compounds to be applied in the method of the present invention maybe administered with at least one other compound. The compounds may beadministered simultaneously, either as separate formulations or combinedin a unit dosage form, or administered sequentially. It is thus alsocontemplated that one compound may be administered intravenously forexample in combination with another compound that is administeredorally.

Clinical Indications

As described herein above the present invention relates to treatmentand/or prevention of organ failure, wherein organ failure is defined asaltered organ function in a critically ill patient requiring medicalintervention to achieve homeostasis. Organ failure includes as usedherein MOF and TAMOF, in at least one organ, such as in at least two,three, four or five organs.

Furthermore, the compounds and/or pharmaceutical compositions describedherein are also suitable for prophylaxis, reduction and/or treatment ofany conditions and/or diseases associated with systemic inflammation(low-grade as well as high-grade) and/or enhanced platelet and/orendothelial activation and/or dysregulation are suitable for prophylaxisand/or treatment with compounds of the invention.

TABLE 4 Non-exclusive list of conditions associated with systemicinflammation, according to pathology, suitable for prophylaxis and/ortreatment by compounds of the invention. Condition Pathology InfectionsAny microorganism (bacteria (intra-, extracellular, myco-), virus,fungi, parasites, prions) Non-infectious antigens Organ/stem celltransplantation, blood transfusion, biological drugs Trauma Blunt,penetrating trauma, polytrauma, neurotrauma, minor, major Burns/freezeburns Organ/tissue Pancreatitis destruction/degeneration/ Irradiationdamage Ischemia Atherosclerosis, thrombi, emboli (cholesterol, fat, air,septic, tissue, foreign body, amniotic fluid), trauma, vascularocclusion, vasculitis, aneurysms, severe anemia Haemorrhage IntoxicationAlcohol, recreational drugs, iatrogenic (chemotherapy, overdose,interaction, adverse event), snake/insect bites MalignancyMyeloproliferative/lymphoproliferative malignancies, solid tumorsmetastasis

TABLE 5 Non-exclusive list of conditions and/or diseases associated withsystemic inflammation, according to medical speciality and/or anatomicallocalization, suitable for prophylaxis and/or treatment by compounds ofthe invention. Conditions and/or diseases associated with systemicinflammation Medical speciality and/or anatomical localization Thefollowing manifestations whatever SIRS, compensatory anti-inflammatorytheir cause response syndrome (CARS), shock, organ failure, MOF, DIC,coagulopathy Microthrombi/emboli/occlusion (imminent, suspected,manifest) in one or more organs Severe infections caused by any Sepsis,severe sepsis, septic shock, organ microorganism including failure, MOF,DIC Necrotisizing fasciitis Surgery, trauma and/or burns including SIRS,compensatory anti-inflammatory response syndrome, Shock, tissuehypoperfusion, base deficit, lactate acidosis, MOF, DIC, coagulopathy(hypercoagulability, hypocoagulability, hyperfibrinolysis) Malignantdiseases and Solid tumours, haematological malignancies,chemotherapeutic/immunosuppressive metastatic tumours Chemotherapy(Alkylating treatment agents (L01A) examplified by Cisplatin,carboplatin and oxaloplatin; Anti-metabolites (L01B) masquerade aspurine ((azathioprine, mercaptopurine)) or pyrimidine; Plant alkaloidsand terpenoids (L01C) as examplified by Vincristine, Vinblastine,Vinorelbine, Vindesine, Podophyllotoxin. Taxanes (L01CD), Taxol,Docetaxel. Topoisomerase inhibitors (L01CB and L01XX) topotecan,irinotecan, amsacrine, etoposide, etoposide phosphate, teniposide.Antitumour antibiotics (L01D) dactinomycin, doxorubicin, epirubicin,bleomycin. Monoclonal antibodies such as trastuzumab, cetuximab,rituximab, Bevacizumab Irradiation and/or irradiation therapy(Conventional external beam radiotherapy, Virtual simulation,3-dimensional conformal radiotherapy, and intensity- modulatedradiotherapy, Radioisotope Therapy (RIT)) Transplantation and theircomplications Solid organs (heart, lungs, liver, kidneys, pancreas,intestines or any combination hereof), allogenic or autologoushaematopoietic stem cells, bone marrow, T- cells, B-cells Graft versushost disease (acute, chronic), graft rejection (host vs. graft)Extracorporeal circulation, vascular Cardiopulmonary bypass, ECMO,ventricular prosthesis and/or apheresis treatment assist devices,non-biologic valvular prosthesis, vascular prosthesis (biological, non-biological) in any location in the human organism Plasmapheresis,leukapheresis, dialysis, renal replacement therapy Toxins Spider, snake,scorpion, jellyfish, wasp, bee, poison dart frog, honeybee, Cyanotoxins,Pit vipers, such as rattlesnakes Neurological diseases Degenerativediseases (Parkinson′s disease, Alzheimer′s disease), Stroke, Neurotrauma(brain, spinal cord), Seizure disorders (epilepsy), Malignancies(brain/spinal cord tumors), Infections (meningitis, encephalitis)Cardiovascular diseases Angina, Atherosclerosis, Cardiomyopathy,Congestive heart failure, Coronary artery disease, Carotid arterydisease, Endocarditis, Heart attack (coronary thrombosis, myocardialinfarction), Hypertension, Hypercholesterolemia/hyperlipidemia,Peripheral artery disease, Stroke Respiratory diseases Asthma,Bronchitis, Emphysema, Chronic obstructive pulmonary disease, Infections(exemplified by influenza, pneumonia and tuberculosis), Malignancies(Lung cancer), Sarcoidosis, Pleurisy Gastrointestinal diseasesInflammatory bowel diseases (Colitis ulcerosa, Mb Crohn′s disease)Hepatic diseases Alcoholic liver disease, Cholangiocarcinoma, Hepatitis,Hepatic encephalopathy, Hepatic failure, Liver abscess, Malignant/benignliver tumours, Liver cirrhosis, Liver coagulopathy, Glycogen storagediseases, Portal hypertension, Primary biliary cirrhosis, Primarysclerosing cholangitis Renal diseases Acute/chronic kidney failure,Acute nephritic syndrome, Atheroembolic renal disease, Chronicnephritis, Nephrotic syndrome, End- stage renal disease, Goodpasturesyndrome, Interstitial nephritis, Kidneycancer/damage/infection/injury/stones, Lupus nephritis,Glomerulonephritis, Membranous nephropathy, Nephroblastoma,Nephrocalcinosis, Nephrogenic diabetes insipidus, Nephropathy - IgA,Polycystic kidney disease, Reflux nephropathy, Renal papillary necrosis,Renal tubular acidosis Endocrine diseases Adrenal disorders (Adrenalinsufficiency, Addison′s disease, Mineralocorticoid deficiency, Conn′ssyndrome, Cushing′s syndrome, Pheochromocytoma, Adrenocorticalcarcinoma) Glucose homeostasis disorders (Diabetes mellitus,Hypoglycemia, Idiopathic hypoglycemia, Insulinoma) Metabolic bonedisease Pituitary gland disorders (Diabetes insipidus, Hypopituitarism(or Panhypopituitarism), Pituitary tumors, Hyperprolactinemia,Acromegaly, gigantism, Cushing′s disease Parathyroid gland disorders(Primary/Secondary/Tertiary hyperparathyroidism, Hypoparathyroidism,Pseudohypoparathyroidism) Menstrual function or fertility disorders(Polycystic ovary syndrome) Thyroid disorders (Goiter, Hyperthyroidismand Graves- Basedow disease, Hypothyroidism, Thyroiditis, Thyroidcancer, Tumours of the endocrine glands, Multiple endocrine neoplasia,Autoimmune polyendocrine syndromes) Gynaecologic/obstetric diseasesObstetric complications (Preeclampsia, eclampsia, HELLP syndrome,amniotic fluid embolism, abruptio placentae) Orthopedic diseases Trauma,Surgery, Fractures, Malignancies of bone, cartilage and soft tissuesincluding Multiple Myeloma, Arthritis (Osteoarthritis, Rheumatoidarthritis), Cerebral Palsy, Osteonecrosis, Gout, Infections, Myasthenia,Osteoporosis, Pagets disease, Spondylitis Haematological diseasesMalignant (Leukaemia, Myelodysplastic syndrome) Non-malignant(Thrombotic thrombocytopenic purpura, haemolytic- uraemic syndrome,aplastic anaemia, Hemophagocytic Lymphohistiocytosis) Infectiousdiseases caused by any Infections caused by any microorganism in themicroorganism exemplified by bacteria cardiovascular, respiratory,renal, (intra-,extracellular, myco-), virus, haematological,neurological, gastrointestinal, fungi, parasites, prions) hepatic andmusculoskeletal organs, such as heart, vessels, microvasculature, lungs,kidney, bone marrow, brain, gut, pancreas, liver, bones, joints andmuscles Endocarditis, Meningitis, Encephalitis, Diarrhea, Hepatitis,Urinary Tract Infections, Intra-Abdominal Infections, Pneumonia,Pharyngitis, Joint Infections, Skin and Soft Tissue infections Allergicdiseases Anaphylaxis, asthma, eosinophil esophagitis, food allergy,urticaria, insect sting allergy, rhinitis, sinusitis, immunodeficiency,mastocytosis Immunologic/rheumatologic diseases Systemic autoimmunediseases (Rheumatoid arthritis (juvenile and/or adult form), systemiclupus erythro- matosis, sclerodermia, antiphospholipid antibodysyndrome, polymyositis, mixed connective tissue disease), Sjogrenssyndrome, Fibromyalgia), Sarcoidosis, Vasculitis (Behcet′s Disease,Buerger′s Disease, Central Nervous System Vasculitis, Churg-StraussSyndrome, Cryoglobulinemia, Giant Cell Arteritis, Henoch-SchonleinPurpura, Microscopic Polyangiitis, Polyarteritis Nodosa, PolymyalgiaRheumatica, Rheumatoid Vasculitis, Takayasu′s Arteritis, Wegener′sGranulomatosis) Inherited disorders Any identified and/or suspectedgenetic defects accompanied with disease

Accordingly, in one embodiment the present invention relates to a methodof treating a critically ill patient, wherein said patient is atincreased risk of acquiring organ failure as defined above byadministering one or more compounds as discussed above belonging to oneor more of the classes:

1. Platelet inhibitors

2. Agents modulating/preserving endothelial integrity

3. Pro-fibrinolytic compounds

4. Inhibitors against TAFIa

Optionally combined with further compounds.

The increased risk of organ failure may be judged by the clinicalappearance of the patient and/or standard laboratory tests. Furthermore,the critically ill patient may additionally be evaluated by TEG/ROTEM asdescribed herein below as being at risk of acquiring organ failure asdiscussed above. In particular if the critically ill patient isdiagnosed as being hypocoagulable or hypercoagulable, such as whenevaluated by TEG/ROTEM, the patient is considered at increased risk ofacquiring organ failure.

The patient may be critically ill due to a variety of diseases andconditions, and a non-exhaustive list of clinical conditions associatedwith systemic inflammation and hence increased risk of organ failure ispresented above in Tables 4 and 5.

In one embodiment, the invention thus relates to administration of acompound inhibiting any of the platelet receptors and/or intracellullarpathways mediating platelet activation, alone or in combination withendothelial modulators and/or pro-fibrinolytics and/or TAFIa-inhibitors,as outlined above for the treatment or prophylaxis of systemicinflammation and/or organ failure in patients with any of the disordersdescribed in tables 4 and 5.

In yet another embodiment, the invention thus relates to administrationof a compound modulating the vascular endothelium through any of theendothelial receptors and/or intracellullar pathways mediatingendothelial activation, alone or in combination with platelet inhibitorsand/or pro-fibrinolytics and/or TAFIa-inhibitors, as outlined above forthe treatment or prophylaxis of systemic inflammation and/or organfailure in patients with any of the disorders described in tables 4 and5.

In another embodiment, the invention thus relates to administration of acompound enhancing and/or modulating fibrinolysis through any of thepathways described above, alone or in combination with TAFIa-inhibitors,as outlined above for the treatment or prophylaxis of systemicinflammation and/or organ failure in patients with any of the disordersdescribed in tables 4 and 5.

Thus, one aspect of the invention relates to a pharmaceuticalcomposition comprising one or more of a platelet inhibitor, anendothelial modulator, pro-fibrinolytics and TAFIa-inhibitors eitheradministered alone or in combination of two or three or four compoundsfor prevention and/or treatment of imminent, suspected or manifest organfailure, wherein organ failure is defined as clinical and/orparaclinical suspected organ dysfunction and/or as altered organfunction in an acutely ill patient requiring medical intervention toachieve homeostasis; organ failure includes as used herein MOF and TAMOFin at least one organ, such as in at least two, three, four, five or sixorgans.

In a particular embodiment the organ failure is due to systemicinflammation or due to severe infections or due to sepsis or due to SIRSand/or CARS or due to coagulopathy or due to trauma and/or burns or dueto malignant diseases such as haematological malignancies, solid tumoursand metastatic tumours or due to ischemia or due to cardiovascularthromboembolic diseases or due to intoxication.

In a further particular embodiment the organ or organs, which aresubject to failure are selected from the group consisting ofcardiovascular, respiratory, renal, haematological, neurological,gastrointestinal and hepatic organs and musculoskeletal, such as heart,vessels, microvasculature, lungs, kidney, bone marrow, brain, gut,pancreas, liver, bones, joints and muscles.

Identification of Critically Ill Patients Using TEG

Another aspect of the present invention relates to the identification ofcritically ill patients using TEG.

Identification of critically ill patients with the highest risk ofmultiorgan failure (MOF) and treatment of these with interventions thatprotects the endothelium, prevent pathologic thrombus formation in themicrocirculation and preserve platelet number and function may protectthese critically ill patients against development of MOF, bleeding andimmunodeficiency. Importantly, the notion that the prevention ofthrombocytopenia and/or preservation of circulating platelet number andfunction may be a tool to avoid MOF and immunodeficiency is a shift inthe paradigm and based on the emerging role of platelets in the hostdefence and the inflammatory response where they contribute directly toclear infections and cooperate with and coordinate the function ofclassical immune cells.

The introduction of the cell based model of haemostasis has emphasizedthe pivotal role of platelets and the kinetics of thrombin generationfor clot development and stability. Together with the finding that theresults of the TEG analysis correlate with the individuals ability togenerate thrombin an increased interest in this whole blood analysis hasrevived [Ganter et al. 2008]. The TEG method is described below.

Viscoelastical Citrated Whole Blood Haemostasis Assay:Thrombelastoqraphy (TEG) or Thrombelastometry (ROTEM)

The TEG in vitro assay is suitable for determining important parametersin the clotting activity and clot strength. The TEG system's approach tomonitoring patient haemostasis is based on the premise that the endresult of the haemostatic process is the clot. The clot's physicalproperties determine whether the patient will have normal hemostasis, orwill be at increased risk for haemorrhage or thrombosis [Salooja et al.2001].

The TEG analyzer uses a small whole blood sample in a rotating cup and apin suspended in the blood by a torsion wire, which is monitored formotion. To speed up the clot formation, a standardized amount of anactivator of coagulation (e.g. Kaolin, tissue factor) may be added tothe cup just before the pin is placed in the cup. The torque of therotating cup is transmitted to the immersed pin only after fibrin and/orfibrin-platelet bonding has linked the cup and pin together. Thestrength and rate of these bonds affect the magnitude of the pin motionsuch that strong clots move the pin directly in phase with cup motion.Thus, the TEG technology documents the interaction of platelets with theprotein coagulation cascade from the time of placing the blood in theanalyzer until initial fibrin formation, clot rate strengthening andfibrin-platelet bonding via GPIIb/IIIa, through eventual clot lysis. TheTEG R parameter reflects the initiation phase, reaction time, from startof coagulation until the first fibrin band is formed; the Angle (a)represents the increase in clot strength, clot kinetics, correlatingwith the thrombin generation. The maximal amplitude (MA) parameterreflects maximal clot strength i.e. the maximal elastic modus of theclot. Ly30 demonstrate the proportion of the clot that is dissolved 30min after MA is reached, reflecting fibrinolysis.

The clot strength and stability and changes herein may be measured asincreases in relative clot strength by the TEG (Thrombelastography)measurable parameter MA and clot stability by the TEG derivableparameter Lysis AUC. The maximal amplitude (MA) parameter reflectsmaximal clot strength i.e. the maximal elastic modus of the clot. Thearea under the lysis curve, i.e. area under the curve from MA isobtained (Lysis AUC) reflects degree of fibrinolysis. Both clot strengthand stability may be measured, or one parameter only may be followedduring a procedure such as either the clot stability or the clotstrength. It is an object of the present invention that the clotstrength measured by the MA increases relative to the MA prior toadministration of a pro-haemostatic agonist by 105%, such as by 110%,such as by 115%, such as by 120%, such as by 125%, such as by 130%, suchas by 135%, such as by 140%, such as by 145%, such as by 150%, such asby 155%, such as by 160%, such as by 165%, such as by 170%, such as by175%, such as by 180%, such as by 185%, such as by 190%, such as by195%, such as by 200% or more. Likewise it is an object of the presentinvention that the clot stability increases Lysis AUC. This parametermay with a TEG analysis be measured e.g. after addition of tissueplasminogen activator (tPA), and thus it is an object of the presentinvention that the clot stability measured by the Lysis AUC increasesrelative to the Lysis AUC prior to administration of a sympathicomimeticagonist by 105%, such as by 110%, such as by 115%, such as by 120%, suchas by 125%, such as by 130%, such as by 135%, such as by 140%, such asby 145%, such as by 150%, such as by 155%, such as by 160%, such as by165%, such as by 170%, such as by 175%, such as by 180%, such as by185%, such as by 190%, such as by 195%, such as by 200% or more.

The TEG system has been recognized as a uniquely useful tool and hasbeen used extensively in the management of haemostasis during majorsurgical interventions such as liver transplantations [Kang et al 1985]and cardiovascular procedures as well as obstetrics, trauma,neurosurgery, management of deep vein thrombosis, and the monitoring anddifferentiation among platelet GPIIb/IIIa antagonists [Di Benedetto2003]. TEG -guided transfusion therapy aiming at normalising clotstrength (MA) has resulted in a reduction in the use of blood products,a reduction in the rate of re-exploration, prediction of bleeding incardiac surgery. It has also been employed in the monitoring of heartassist devices. The clinical utility of the TEG comes from that thisanalysis identifies and quantifies the patient's ability to generatethrombin and the resulting physical properties of the clot as well asidentifying enhanced fibrinolysis [Rivard et al. 2005].

The data in Example 1 demonstrate that TEG identifies patients atincreased risk of organ failure, including MOF, and mortality earlierthan conventional coagulation analysis, which are included in differentprognostic scores such as the ISTH DIC score. The clinical importance ofthe TEG result is further illustrated by that patients presenting with ahypocoagulable TEG at ICU admission also had significantly increasedAPACHE II score and developed higher maximum SOFA score and increasedcreatinine as compared to patients with a normal TEG upon arrival. SinceTEG, but not platelet count differed upon arrival, TEG is able toreflect changes of pathophysiological significance in the haemostaticsystem earlier and more specifically than routine laboratory parameters.TEG was performed in citrated whole blood and looks beyond the firsttrace amount of fibrin formed. This technique describes the quality andspeed of the entire coagulation and clot formation process. In contrast,commonly used routine laboratory tests are performed in centrifugedplasma fractions and therefore overlook important interactions betweenthe protein coagulation cascade, on the one hand, and platelets andfibrin, on the other hand. The hypocoagulability reflects patients withan increased consumption of platelets that participates in microthrombusformation in vital organs, as illustrated by a higher maximal SOFA scorethan patients presenting with a normal TEG upon ICU admission.

The hypercoagulability reflects an increased activation of thehaemostatic system rendering the platelets hyperreactive, and thus proneto thrombus development.

Identification of Patients at Increased Risk of Development of OrganFailure, Including MOF, by a Viscoelastical Citrated Whole BloodHaemostatic Assay

In one embodiment, the invention thus relates to a method of identifyingcritically ill patients at increased risk of development of organfailure including MOF and TAMOF by analyzing a citrated whole bloodsample, such as in a citrated whole blood sample activated by kaolin,such as in a citrated whole blood sample activated by tissue factor,such as in a native whole blood sample, such as a native whole bloodsample activated by kaolin, such as in a citrated whole blood sampleactivated by tissue factor from the patient by a cell basedviscoelastical assay upon arrival at the ICU.

In one embodiment, the invention thus relates to a method of identifyingcritically ill patients at increased risk of development of TAMOF byanalyzing a citrated whole blood sample from the patient by thethrombelastography (TEG) system.

In one embodiment, the invention thus relates to a method of identifyingcritically ill patients at increased risk of development of TAMOF byanalyzing a citrated whole blood sample from the patient by thethrombelastometry (ROTEM) systems.

In one embodiment, the invention thus relates to a method of identifyinghypocoagulable critically ill patients at risk of development of TAMOFby analyzing a whole blood sample from the patient by thethrombelastography (TEG) and/or thrombelastometry (ROTEM) system.

In one embodiment, the invention thus relates to a method of identifyinghypercoagulable critically ill patients at risk of development of TAMOFby analyzing a citrated whole blood sample from the patient by thethrombelastography (TEG) and/or the thrombelastometry (ROTEM) system.

Items

In one embodiment, the invention thus relates to a compositioncomprising one or more platelet inhibitors and one or more compoundscapable of augmenting the fibrinolytic activity.

In one embodiment, the invention thus relates to a compositioncomprising one or more platelet inhibitors and one or more TAFIainhibitors.

In one embodiment, the invention thus relates to a compositioncomprising one or more compounds capable of modulating/preserving theendothelial integrity and one or more compounds capable of augmentingthe fibrinolytic activity.

In one embodiment, the invention thus relates to a compositioncomprising one or more compounds capable of modulating/preserving theendothelial integrity and one or more TAFIa inhibitors.

In one embodiment, the invention thus relates to a composition whereinthe platelet inhibitor capable of inhibiting the platelet GPIIb/IIIareceptor is administered together with an inhibitor of thromboxanesynthase.

In one embodiment, the invention thus relates to a composition, whereinthe platelet inhibitor is capable of inhibiting the platelet COX1 and/orCOX2 pathways such as salicylates, arylalkanoic acids, 2-Arylpropionicacids, N-Arylanthranilic acids, pyrazolidine derivatives and oxicams.

In one embodiment, the invention thus relates to a composition whereinthe platelet inhibitor is capable of inhibiting Thromboxane-synthase,such as Flavonoids, such as Apigenin, and TP-antagonists such asSQ29548, Bay u 3405, BM 13.177.

In one embodiment, the invention thus relates to a composition whereinthe platelet inhibitor is capable of inhibiting adenosine uptake in theplatelets such as dipyramidol such as Persantin, Asasantin, Aggrenox.

In one embodiment, the invention thus relates to a composition whereinthe platelet inhibitor is capable of inhibiting the platelet GPIbreceptor, such as mAB Ib-23, mAB 6B4, R9alpha557 peptide,aurintricarboxylic acid (ATA), crotalin, agkistin, peptide(Trp-Ile-Arg-Arg-Pro-Phe-Phe-Pro-Phe) from alpha B-crystallin

In one embodiment, the invention thus relates to a composition whereinthe platelet inhibitor is capable of inhibiting the platelet GPVIreceptor, such as EXP3179, triplatin-1 and -2, JAQ1, mAB 10B12, mAB 1C3,mAb 12G1.

In one embodiment, the invention thus relates to a composition whereinthe platelet inhibitor is capable of inhibiting the platelet PARreceptors, such as thrombin inhibitors, heterocycle-basedpeptide-miimetic antagonists of PAR-1, RWJ-56110 and RWJ-58259, SCH79797 SCH 203099 and PAR4 antagonists such astrans-cinnamoyl-YPGKF-amide (tc-Y-NH(2)) and palmitoyl-SGRRYGHALR-amide(P4pal10), PAR-2 antagonist ENMD-1068, PAR2 monoclonal antibody SAM-11.

In one embodiment, the invention thus relates to a composition whereinthe platelet inhibitor is Phosphodiesterase inhibitor PDE3 such asCilostazol.

In one embodiment, the invention thus relates to a composition whereinthe platelet inhibitor is Nitroaspirin (NCX4016).

In one embodiment, the invention thus relates to a composition whereinthe platelet inhibitor is a Polyethylene Glycol-Conjugated Albumin.

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis selected from the group consisting of CD39 and CD73.

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis a compound involved in redox control of endothelial functions.

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis selected from the group consisting of L-Arginine andtetrahydrobiopterin, Antioxidants (Ascorbate, Glutathione,.alpha.-tocopherol, ubiquinol-10, Probucol), Iron chelators, Polyphenols

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis selected from the group consisting of HMG-CoA reductase inhibitors(Fluvastatin, Lovastatin, Pravastatin, Simvastatin),Angiotensin-receptor antagonists and ACE inhibitors (Captopril,Zofenopril, Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril,Benazepril, Fosinopril, Casokinins, lactokinins), Peroxisomeproliferator-activated receptors (PPARs), NADPH oxidase, Xanthineoxidase, PETN, Heparan sulfates (PI-88), heparan sulfate mimetics,Activators of oxidized/heme-free sGC (BAY 58-2667), Anti-PECAM/SOD.

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis Honokiol.

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis a compound that directly modulates endothelial barrier functionthrough modulating effects on sphingosine-1-phosphate (S1P)-receptors.

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis selected from the group consisting of TY720, AA-R, AAL-S, KRP-203,AUY954, CYM-5442, SEW2871, W146, W140, VPC44116, VPC23019, JTE-013).

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis an antibody and/or another molecule against/antagonizing histonesthrough their inhibition histone-mediated endothelial damage and/ormicrothrombi formation and/or fibrin deposition.

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis a compound enhancing the natural anticoagulant pathways and henceprotecting the endothelium such as but not exclusively: Protein Cpathway (Activated protein C (APC, Drotrecogin alfa), protein C,compounds that either mimics and/or protects from degradation and/orenhances soluble thrombomodulin and/or EPCR and/or protein S),Antithrombin III (ATIII) (or ATIII like compounds and/or compounds thatenhance ATIII function) and tissue factor pathway inhibitor (TFPI) (orTFPI compounds and/or compounds that enhance TFPI function).

In one embodiment, the invention thus relates to a composition whereinthe compound capable of modulating/preserving the endothelial integrityis a compound that maintain and/or promote Gβγ function and/orsignalling following endothelial PAR activation to ensure reannealing ofadherens junctions opened following inflammatory PAR mediated activationof Ga.

In one embodiment, the invention thus relates to a composition whereinthe compound capable of augmenting the fibrinolytic activity is selectedfrom the group consisting of tissue plasminogen activators such as:Alteplase, Tenecteplase, Reteplase, Streptokinase.

In one embodiment, the invention thus relates to a TAF1a inhibitor forprevention or treatment of organ failure, including multi organ failure,defined as microthrombosis in at least one organ, such as in at leasttwo organs.

In one embodiment of the invention the TAF1a inhibitor is selected fromthe group consisting of CPU-1, AZD9684, MERGETPA, Compound 21(UK-396,082).

In one embodiment of the invention the compound capable of inhibitingthe platelet GPIIb/IIIa receptor is administered together with aninhibitor of thromboxane synthase.

In one embodiment of the invention the platelet inhibitor is capable ofinhibiting the platelet COX1 and/or COX2 pathways such as salicylates,arylalkanoic acids, 2-Arylpropionic acids, N-Arylanthranilic acids,pyrazolidine derivatives and oxicams. 55-60

In one embodiment of the invention the platelet inhibitor is capable ofinhibiting Thromboxane-synthase, such as Flavonoids, such as Apigenin,and TP-antagonists such as SQ29548, Bay u 3405, BM 13.177.

In one embodiment of the invention the platelet inhibitor is capable ofinhibiting adenosine uptake in the platelets such as dipyramidol such asPersantin, Asasantin, Aggrenox.

In one embodiment of the invention the platelet inhibitor is capable ofinhibiting the platelet GPIb receptor, such as mAB Ib-23, mAB 6B4,R9alpha557 peptide, aurintricarboxylic acid (ATA), crotalin, agkistin,peptide (Trp-Ile-Arg-Arg-Pro-Phe-Phe-Pro-Phe) from alpha B-crystallin

In one embodiment of the invention the platelet inhibitor is capable ofinhibiting the platelet GPVI receptor, such as EXP3179, triplatin-1 and-2, JAQ1, mAB 10B12, mAB 1C3, mAb 12G1.

In one embodiment of the invention the platelet inhibitor is capable ofinhibiting the platelet PAR receptors, such as thrombin inhibitors,heterocycle-based peptide-miimetic antagonists of PAR-1, RWJ-56110 andRWJ-58259, SCH 79797 SCH 203099 and PAR4 antagonists such astrans-cinnamoyl-YPGKF-amide (tc-Y-NH(2)) and palmitoyl-SGRRYGHALR-amide(P4pal10), PAR-2 antagonist ENMD-1068, PAR2 monoclonal antibody SAM-11.

In one embodiment, the invention thus relates to a compound capable ofaugmenting the fibrinolytic activity in whole blood for prevention ortreatment of organ failure, wherein organ failure is defined as alteredorgan function in an acutely ill patient requiring medical interventionto achieve homeostasis; organ failure includes as used herein MOF andTAMOF, in at least one organ, such as in at least two, three, four orfive organs.

In one embodiment of the invention the compound capable of augmentingthe fibrinolytic activity in whole blood is selected from the groupconsisting of tissue plasminogen activators such as: Alteplase,Tenecteplase, Reteplase, Streptokinase.

In one embodiment, the invention thus relates to a TAF1a inhibitor forprevention or treatment of organ failure, including multi organ failure,wherein organ failure is defined as altered organ function in an acutelyill patient requiring medical intervention to achieve homeostasis; organfailure includes as used herein MOF and TAMOF, in at least one organ,such as in at least two, three, four or five organs.

In one embodiment of the invention the TAF1a inhibitor is selected fromthe group consisting of CPU-1, AZD9684, MERGETPA, Compound 21(UK-396,082).

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with malignant diseasessuch as, but not limited to, solid tumours, haematological malignancies,metastatic tumours,

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients undergoingtransplantation. With transplantation means solid organs such as heart,lungs, liver, kidneys, pancreas, intestines or any combination hereof.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients undergoing transplantationof allogenic or autologous haematopoietic stem cells, bone marrow,T-cells, B-cells are referred to. Furthermore treatment of acomplication of allogenic transplantation, graft versus host diseaseand/or graft rejection (host vs. graft) is included herein.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients secondary toextracorporeal circulation such as but not limited to patientsundergoing cardiopulmonary bypass, on ECMO treatment, receivingventricular assist devices, receiving non-biologic valvular prosthesis.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with vascular prosthesisin any location in the human organism.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with autoimmune diseasessuch as but not limited to rheumatoid arthritis (juvenile and/or adultform), systemic lupus erythromatosis, sclerodermia, antiphospholipidantibody syndrome.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with colitis ulcerosa orMb Crhohn's disease.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with necrotisizingfasceitis.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with burn trauma.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients exposed to irradiation.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with obstetriccomplications such as but not limited to preeclampsia, HELLP syndrome.

In one embodiment the organ failure is due to reperfusion injuryfollowing ischemia.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with systemic inflammatoryresponse syndrome.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with acute vascularocclusions such as but not limited to mesenteric thrombosis.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with haemolytic-uraemicsyndrome.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with systemic infections(any agent) such as but not limited to bacteria, mycoplasma,mycobacteria, ricketsiae, viral, fungal, protozoal infections.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF after surgery or trauma.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with vasculitis such as,but not limited to Behcet's Disease, Buerger's Disease, Central NervousSystem Vasculitis, Churg-Strauss Syndrome, Cryoglobulinemia, Giant CellArteritis, Henoch-Schonlein Purpura, Microscopic Polyangiitis,Polyarteritis Nodosa, Polymyalgia Rheumatica, Rheumatoid Vasculitis,Takayasu's Arteritis, Wegener's Granulomatosis.

In one embodiment, the invention thus relates to a compound for thetreatment or prophylaxis of TAMOF in patients with toxins, such as, butnot limited to spider, snake, scorpion, jellyfish, wasp, bee, poisondart frog, honeybee, Cyanotoxins, Pit vipers, such as rattlesnakes.

In one embodiment, the invention thus relates to a method for thetreatment or prophylaxis of TAMOF in patients treated with chemotherapysuch as but not limited to alkylating agents (L01A) exemplified byCisplatin, carboplatin and oxaloplatin; Anti-metabolites (L01B)masquerade as purine ((azathioprine, mercaptopurine)) orpyrimidine—which become the building blocks of DNA; Plant alkaloids andterpenoids (L01C) as exemplified by Vincristine, Vinblastine,Vinorelbine, Vindesine, Podophyllotoxin. Taxanes (L01CD) Taxol,Docetaxel. Topoisomerase inhibitors (L01CB and L01XX) topotecan.,irinotecan, amsacrine, etoposide, etoposide phosphate, teniposide.Antitumour antibiotics (L01D) dactinomycin, doxorubicin, epirubicin,bleomycin. Monoclonal antibodies such as trastuzumab, cetuximab,rituximab, Bevacizumab.

In one embodiment, the invention thus relates to a method for thetreatment or prophylaxis of TAMOF in patients treated with irradiationtherapy such as but not limited to conventional external beamradiotherapy, Virtual simulation, 3-dimensional conformal radiotherapy,and intensity-modulated radiotherapy, Radioisotope Therapy (RIT).

In one embodiment, the invention thus relates to compound, hereindefined as a pharmaceutical composition comprising one or more of aplatelet inhibitor, an endothelial modulator, pro-fibrinolytics andTAFIa-inhibitors either administered alone or in combination of two orthree or four compounds for prevention and/or treatment of imminent,suspected or manifest organ failure, wherein organ failure is defined asclinical and/or paraclinical suspected organ dysfunction and/or asaltered organ function in an acutely ill patient requiring medicalinvention to achieve homeostasis; organ failure includes as used hereinMOF and TAMOF in at least one organ, such as in at least two, three,four, five or six organs.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to systemicinflammation or due to severe infections or due to sepsis or due to SIRSand/or CARS or due to coagulopathy or due to trauma (Blunt, penetratingtrauma, polytrauma, neurotrauma, minor, major) and/or burns/freezingburns or due to malignant diseases such as haematological malignancies,solid tumours and metastatic tumours or due to ischemia/haemorrhage ordue to cardiovascular thromboembolic diseases or due to intoxication.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organs, which are subject to failure areselected from the group consisting of cardiovascular, respiratory,renal, haematological, neurological, gastrointestinal and hepatic organsand musculoskeletal, such as heart, vessels, microvasculature, lungs,kidney, bone marrow, brain, gut, pancreas, liver, bones, joints andmuscles.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to Infectious diseasescaused by any microorganism exemplified by bacteria (intra-,extracellular, myco-), virus, fungi, parasites, prions) includinginfections caused by any microorganism in the cardiovascular,respiratory, renal, haematological, neurological, gastrointestinal,hepatic and musculoskeletal organs, such as heart, vessels,microvasculature, lungs, kidney, bone marrow, brain, gut, pancreas,liver, bones, joints and muscles Endocarditis, Meningitis, Encephalitis,diarrhea, Hepatitis, Urinary Tract Infections, Intra-AbdominalInfections, Pneumonia, Pharyngitis, Joint Infections, Skin and SoftTissue infections.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to ischemia due tostherosclerosis, thrombi, emboli (cholesterol, fat, air, septic, tissue,foreign body, amniotic fluid), trauma, vascular occlusion, vasculitis,aneurysms, severe anemia and/or microthrombi/emboli/occlusion (imminent,suspected, manifest) in one or more organs or severe infections causedby any microorganism including sepsis, severe sepsis, septic shock,organ failure, MOF, DIC, necrotisizing fasciitis.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to surgery, traumaand/or burns including SIRS, compensatory anti-inflammatory responsesyndrome, Shock, tissue hypoperfusion, base deficit, lactate acidosis,MOF, DIC, coagulopathy (hypercoagulability, hypocoagulability,hyperfibrinolysis).

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to malignant diseasesand chemotherapeutic/immunosuppressive treatment, solid tumours,haematological malignancies, metastatic tumours.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to chemotherapy(Alkylating agents (L01A) exemplified by Cisplatin, carboplatin andoxaloplatin; Anti-metabolites (L01B) masquerade as purine((azathioprine, mercaptopurine)) or pyrimidine; Plant alkaloids andterpenoids (L01C) as exemplified by Vincristine, Vinblastine,Vinorelbine, Vindesine, Podophyllotoxin. Taxanes (L01CD) Taxol,Docetaxel. Topoisomerase inhibitors (L01CB and L01XX) topotecan,irinotecan, amsacrine, etoposide, etoposide phosphate, teniposide.Antitumour antibiotics (L01D) dactinomycin, doxorubicin, epirubicin,bleomycin.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to monoclonalantibodies such as trastuzumab, cetuximab, rituximab, Bevacizumab.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to irradiation and/orirradiation therapy (Conventional external beam radiotherapy, Virtualsimulation, 3-dimensional conformal radiotherapy, andintensity-modulated radiotherapy, Radioisotope Therapy (RIT))

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to transplantation(heart, lungs, liver, kidneys, pancreas, intestines or any combinationhereof), allogenic or autologous haematopoietic stem cells, bone marrow,T-cells, B-cells and their complications such as graft versus hostdisease (acute, chronic), graft rejection (host vs. graft).

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to extracorporealcirculation, plasmapheresis, leukapheresis, dialysis, renal replacementtherapy, vascular prosthesis and/or apheresis treatment, cardiopulmonarybypass, ECMO, ventricular assist devices.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to non-biologicvalvular prosthesis, vascular prosthesis (biological, non-biological) inany location in the human organism.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to intoxication withalcohol, recreational drugs, iatrogenic (chemotherapy, overdose,interaction, adverse event), snake/insect bites (spider, snake,scorpion, jellyfish, wasp, bee, poison dart frog, honeybee),cyanotoxins, Pit vipers, such as rattlesnakes.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to cardiovasculardiseases like but not exclusively Angina, Atherosclerosis,Cardiomyopathy, Congestive heart failure, Coronary artery disease,Carotid artery disease, Endocarditis, Heart attack (coronary thrombosis,myocardial infarction), Hypertension,Hypercholesterolemia/hyperlipidemia, Peripheral artery disease, Stroke,reperfusion injury following ischemia.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to systemic autoimmunediseases (Rheumatoid arthritis (juvenile and/or adult form), systemiclupus erythromatosis, sclerodermia, antiphospholipid antibody syndrome,polymyositis, mixed connective tissue disease), Sjogrens syndrome,Fibromyalgia), Sarcoidosis.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to vasculitis (Behcet'sDisease, Buerger's Disease, Central Nervous System Vasculitis,Churg-Strauss Syndrome, Cryoglobulinemia, Giant Cell Arteritis,Henoch-Schonlein Purpura, Microscopic Polyangiitis, PolyarteritisNodosa, Polymyalgia Rheumatica, Rheumatoid Vasculitis, Takayasu'sArteritis, Wegener's Granulomatosis).

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to allergic diseasesincluding Anaphylaxis, asthma, eosinophil esophagitis, food allergy,urticaria, insect sting allergy, rhinitis, sinusitis, immunodeficiency,mastocytosis.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to respiratory diseasesincluding Asthma, Bronchitis, Emphysema, Chronic obstructive pulmonarydisease, Infections (exemplified by influenza, pneumonia andtuberculosis), Malignancies (Lung cancer), Sarcoidosis, Pleurisy.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to Renal diseases suchas Acute/chronic kidney failure, Acute nephritic syndrome, Atheroembolicrenal disease, Chronic nephritis, Nephrotic syndrome, End-stage renaldisease, Goodpasture syndrome, Interstitial nephritis, Kidneycancer/damage/infection/injury/stones, Lupus nephritis,Glomerulonephritis, Membranous nephropathy, Nephroblastoma,Nephrocalcinosis, Nephrogenic diabetes insipidus, Nephropathy-IgA,Polycystic kidney disease, Reflux nephropathy, Renal papillary necrosis,Renal tubular acidosis.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to Hepatic diseasessuch as Alcoholic liver disease, Cholangiocarcinoma, Hepatitis, Hepaticencephalopathy, Hepatic failure, Liver abscess, Malignant/benign livertumours, Liver cirrhosis, Liver coagulopathy, Glycogen storage diseases,Portal hypertension, Primary biliary cirrhosis, Primary sclerosingcholangitis.

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to Endocrine diseaseslike Adrenal disorders (Adrenal insufficiency, Addison's disease,Mineralocorticoid deficiency, Conn's syndrome, Cushing's syndrome,Pheochromocytoma, Adrenocortical carcinoma), Glucose homeostasisdisorders (Diabetes mellitus, Hypoglycemia, Idiopathic hypoglycemia,Insulinoma), Metabolic bone disease, Pituitary gland disorders (Diabetesinsipidus, Hypopituitarism (or Panhypopituitarism), Pituitary tumors,Hyperprolactinemia, Acromegaly, gigantism, Cushing's disease,Parathyroid gland disorders (Primary/Secondary/Tertiaryhyperparathyroidism, Hypoparathyroidism, Pseudohypoparathyroidism),Menstrual function or fertility disorders (Polycystic ovary syndrome),Thyroid disorders (Goiter, Hyperthyroidism and Graves-Basedow disease,Hypothyroidism, Thyroiditis, Thyroid cancer, Tumours of the endocrineglands, Multiple endocrine neoplasia, Autoimmune polyendocrinesyndromes).

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to gastrointestinaldiseases such as Inflammatory bowel diseases (Colitis ulcerosa, MbCrohn's disease).

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due toGynaecologic/obstetric diseases such as Obstetric complications(Preeclampsia, eclampsia, HELLP syndrome, amniotic fluid embolism,abruptio placentae).

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to Neurologicaldiseases such as Degenerative diseases (Parkinson's disease, Alzheimer'sdisease), Stroke, Neurotrauma (brain, spinal cord), Seizure disorders(epilepsy), Malignancies (brain/spinal cord tumors), Infections(meningitis, encephalitis).

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to Haematologicaldiseases such as Malignant (Leukaemia, Myelodysplastic syndrome) and/orNon-malignant (Thrombotic thrombocytopenic purpura, haemolytic-uraemicsyndrome, aplastic anaemia, Hemophagocytic Lymphohistiocytosis).

In one embodiment, the invention thus relates to a compound for thetreatment of or prophylaxis of organ failure due to Orthopedic diseasessuch as Trauma, Surgery, Fractures, Malignancies of bone, cartilage andsoft tissues including Multiple Myeloma, Arthritis (Osteoarthritis,Rheumatoid arthritis), Cerebral Palsy, Osteonecrosis, Gout, Infections,Myasthenia, Osteoporosis, Pagets disease, Spondylitis.

DETAILED DESCRIPTION OF DRAWINGS

FIG. 1: Recording haemostatic activity using Thrombelastography (TEG):TEG records the viscoelastic changes during coagulation by analysis ofwhole blood placed in a rotating cup. A pin is suspended in the bloodfrom a torsion wire, and its resistance to motion is recorded. Fourparameters are routinely reported: R (reaction time) denotes the latencyfrom the time at which the blood is placed in the cup until the clotbegins to form; the angle (Angle) represents the progressive increase inclot strength; the maximum amplitude (MA) reflects the maximal clotstrength; and lysis (Ly30) reflects clot lysis.

FIG. 2: Multiplate whole blood aggregometry is a platelet function test,(Multiplate®, Dynabyte Medical, Munich, Germany). This test is based onmultiple electrode platelet aggregometry (MEA), which measures plateletaggregation in whole blood (WB) after stimulation with selectiveplatelet agonists such as trombinactivated peptide (TRAP), ADP, ASPI andCOLlagen. The increase of impedance by the attachment of platelets ontothe Multiplate sensors is transformed to arbitrary aggregation units(AU) and plotted against time. Multiplate thereby allows analyzing theeffect of antithrombotic drugs like aspirin, clopidogrel andprostacycline on platelet aggregation.

FIG. 3: Comparison of baseline TEG values with samples obtained after60- and 120 min of flolan infusion.

FIG. 4: Comparison of baseline Multiplate values with samples obtainedafter 60- and 120 min of flolan infusion.

EXAMPLES Example 1

It has now surprisingly been found that in critically ill patients theTEG result upon arrival to the ICU predicts 30 and 90-day mortality. In88 medical ICU patients, none of the conventional laboratory analysisincluding APTT, PT, INR, platelet count, D dimer, CRP or haemoglobindiffered at admission between 30-day survivors (n=51) and non-survivors(n=37). The TEG at admission, however, differed significantly betweensurvivors and non-survivors, respectively in all three aspects of thehaemostatic process R 6.4 (±2.7) vs. 8.07 (±3.0), p=0.002; Angle 61.0(±13.1) vs. 51.7 (±18.0),p=0.01; MA 57.3 (±13.0) vs. 49.4(±17.8),p=0.02.

Thus, a prolonged R was associated with a 3.7 (95% Cl 1.3-10.0)increased odds ratio (unadjusted) for 30-day mortality, a decreasedAngle with a 3.8 (95% 1.6-9.5) increased odds ratio (unadjusted) formortality, and a decreased MA with a 2.8 (95% Cl 1.2-6.8) increased oddsratio (unadjusted) for 30-day mortality. Multivariate logisticregression with use of the significant associated variables (age andAPACHE II) was repeated twice for the 88 medical patients identifyingR>8 minutes as an independent risk factor for mortality (adjusted OR3.8; 95% Cl 1.3-11.3) after adjustment for age >65 years (adjusted OR1.9; 95% Cl 0.7-5) and APACHE II >25 (adjusted OR 4.1; 95% Cl 1.6-10.7).Hosmer and Lemeshow Goodness-of-Fit test, p=0.85.

Also MA<50 mm, was an independent risk factor for mortality (adjusted OR3.0; 95% Cl 1.1-8.0) after adjustment for age >65 years (adjusted OR2.5; 95% Cl 0.9-7.2) and APACHE II >25 (adjusted OR 3.5; 95% Cl1.3-9.0). Hosmer and Lemeshow Goodness-of-Fit test, p=0.68. Consequentlya hypocoagulable TEG result upon arrival in these patients may representa therapeutic target.

Furthermore, patients presenting with hypercoagulability defined as aR<4 min and/or Angle>78° and/or MA>69 mm had a higher survival rate thanpatients being hypocoagulable (74% vs. 54%) but a lower survival ratethan patients presenting with a normal TEG result upon ICU admission(74% vs. 87%), emphasizing that perturbations in coagulability, ineither the hypo or hyper direction, have a negative predictive value forclinical outcome in these critically ill patients.

These data demonstrate that TEG identifies patients at increased risk oforgan failure, including MOF, and mortality earlier than conventionalcoagulation analysis, which are included in different prognostic scoressuch as the ISTH DIC score. The clinical importance of the TEG result isfurther illustrated by that patients presenting with a hypocoagulableTEG at ICU admission also had significantly increased APACHE II scoreand developed higher maximum SOFA score and increased creatinine ascompared to patients with a normal TEG upon arrival. Since TEG, but notplatelet count differed upon arrival, TEG is able to reflect changes ofpathophysiological significance in the haemostatic system earlier andmore specifically than routine laboratory parameters. TEG was performedin citrated whole blood and looks beyond the first trace amount offibrin formed. This technique describes the quality and speed of theentire coagulation and clot formation process. In contrast, commonlyused routine laboratory tests are performed in centrifuged plasmafractions and therefore overlook important interactions between theprotein coagulation cascade, on the one hand, and platelets and fibrin,on the other hand. The hypocoagulability reflects patients with anincreased consumption of platelets that participates in microthrombusformation in vital organs, as illustrated by a higher maximal SOFA scorethan patients presenting with a normal TEG upon ICU admission.

The hypercoagulability reflects an increased activation of thehaemostatic system rendering the platelets hyperreactive and thus proneto thrombus development.

Example 2

Ninety-four critically ill patients admitted to the intensive care unit(ICU) underwent haemofiltration with or without concomitant Flolan(prostacyclin) treatment. Flolan was administered in a low dose of 4-6ng/kg/min in the filters to prevent these from clotting and consequentlythere was only a minor spill over of Flolan to the systemic circulation.The patients were retrospectively reviewed.

TABLE 6 Flolan group Non-Flolan group (n = 24) (n = 70) APACHE II score(mean) 26 28 Platelet count (difference before +14 −17 vs. afterhaemofiltration) 90 day survival (%) 67 47 APACHE II: Acute Physiologyand Chronic Health Evaluation II, ICU: Intensive Care Unit

The two groups (Flolan vs. non-flolan) were comparable in regards toAPACHE II at admission. However, patients in the flolan group were moreseverely ill as evaluated by a lower platelet count at start ofhemofiltration, a higher frequency of severe thrombocytopenia, a higherfrequency of DIC diagnoses, a higher maximum SOFA score and a higherSOFA score at hemofiltration initiation as compared to the patientsreceiving non-flolan. The finding of increased total transfusionrequirements and specifically of FFP during hemofiltration in the flolangroup vs. the non-flolan group might thus be attributed to the higherdisease severity and associated coagulopathy and not to an increasedrisk of bleeding due to the use of flolan as anticoagulant. Importantly,when comparing mortality between groups, we found that the flolan grouptended to have decreased mortality at 30 days (21% vs. 39%, p=0.12), 90days (34% vs. 53%, p=0.10) and 365 days (38% vs. 57%, p=0.09).

Flolan does not negatively influence the haemostatic competence asevaluated by transfusion requirements in critically ill patientsundergoing haemofiltration and thereby questions the assumption thatprostacycline is a powerful antithrombotic agent.

Furthermore, the significant decrease in mortality observed inhaemofiltrated patients receiving flolan in the filters indicate thatthe minor systemic spill-over affects the endothelium, limiting thepro-coagulant effects of systemic inflammation and coagulationactivation preventing microvascular occlusion and organ failure.

Example 3

Six healthy volunteers were administered flolan (prostacyclin)intravenously at a dose of 4 ng/kg/min for 2 h. Blood samples for wholeblood viscoelastical assay (Thrombelastography [TEG]) and whole bloodplatelet aggregation (Multiplate) was obtained before infusion ofFlolan, after 60 min infusion of Flolan and after 120 min infusion ofFlolan.

With regard to the TEG assay this was performed as recommended by themanufacturer and 340 μl are mixed with 20 μl CaCl 0.2 M (finalconcentration 11.1 mM in the cup) and kaolin at 37° C. after which thehaemostatic activity is recorded as depicted in FIG. 1.

Whole blood impedance aggregometry analyzed by the Multiple Plateletfunction Analyzer (MultiPlate® analyzer). Analysis employing variousplatelet agonists: ASPItest (activation by arachidonic acid), COLtest(activation by collagen through the collagen receptor), TRAPtest(activation by TRAP-6 stimulates the thrombin receptor on the plateletsurface and ADPtest (activation by ADP stimulates platelet activation bythe ADP receptors).

MultiPlate continuously records platelet aggregation. The increase ofimpedance by the attachment of platelets onto the Multiplate sensors istransformed to arbitrary aggregation units (AU) and plotted against timeas depicted in FIG. 2.

Results:

No significant difference was observed when comparing baseline TEGvalues with samples obtained after 60- and 120 min of flolan infusionfor any of the parameters investigated (R, Angle, MA) in any of the 6volunteers studied, see FIG. 3.

Similarly, no significant difference was observed when comparingbaseline Multiplate values with samples obtained after 60- and 120 minof flolan infusion for any of the agonists investigated (ASPI, COL, ADP,TRAP) in any of the 6 volunteers studied, see FIG. 4.

Conclusions:

Infusion of Flolan at the doses recommended for clinical use did notnegatively affect whole blood haemostatic competence as evaluated byTEG. Furthermore, with regard to whole blood platelet aggregation,employing various platelet agonists is not affected negatively by flolaninfusion indicating that such administration not compromise haemostasis.

Example 4

To test the effect of IV infused GPIIb/IIIa inhibitor and PGI2 onbleeding and thrombosis, a rat endotoxemia model was establishedemploying 12 Sprague Dawley rats, males, 250-300 g. The rats wereanaesthesized and three IV catheters were placed (1 for endotoxininfusion and 1 for each of the 2 study drugs or saline (Placebo)).

Group 1 (n=6): Endotoxin+Drugs

Endotoxin (LPS (Sigma-Aldrich, Cat. No. 2762) from e. coli strain026:B6IV injection (5 mg/kg bolus)

IV infusion for 8 hours with a combination of two test drugs

GPIIb/IIIa inhibitor=abciximab=RheoPro [1 mg/kg bolus and 0.250mikrogram/kg/min]

PGI2=flolan[20 ng/kg/min]

Group 2 (n=6): Endotoxin+Placebo

Endotoxin (LPS (Sigma-Aldrich, Cat. No. 2762) from e. coli strain026:B6) IV injection (5 mg/kg bolus)

IV infusion for 8 hours with saline (placebo)

The animals were sacrificed after 8 hours treatment/placebo afterreceiving a heparin infusion to avoid post-mortem intravascular fibrindeposition.

Analyses before and after treatment/placebo:

-   -   Platelet count, hemoglobin, blood pressure, heart rate

Post-mortem histopathology analyses of bleeding and thrombosis:

-   -   CNS, heart, lungs, liver, kidneys and intestine

Results

Rats receiving the study drugs demonstrated a diminished decline inplatelet count after 8 hours of endotoxin infusion than the placebogroup (−39.4% vs. −63.9%), a diminished increase in heart rate (+4.8%vs. +27.6%) and a diminished drop in blood pressure (+0.7% vs. −20.3%).No differences between groups was found with regard to haemoglobinindicating that the rats treated with the study drug did not bleed Postmortem histopathology demonstrated no evidence of increased bleeding invital organs in the group receiving the study drugs as compared to theplacebo group.

Conclusions

Infusion of a combination of RheoPro (=abciximab=a GPIIb/IIIa inhibitor)and Flolan (prostacyclin) to rats with endotoxaemia resulted in improvedmaintenance of platelet count and reduced clinical deterioration, asevaluated by reduced increase in heart rate and reduced decline in bloodpressure, as compared to rats that received placebo. RheoPro is a potentreversible GPIIb/IIIa platelet inhibitor preventing formation ofplatelet aggregates in the microcirculation. In addition, flolan, aprostacyclin analogue, maintains endothelial integrity and preventsdevelopment of a procoagulant phenotype limiting the interaction betweenplatelets and endothelial cells.

Also, infusion of a combination of RheoPro at a dose twice therecommended dose for humans and Flolan, at a dose 10 times the maximalrecommended dose in humans will not result in an increased bleedingtendency as evaluated by hemoglobin and histopathological examination ofvital organs including CNS, heart, lungs, liver, kidneys and intestine.

TABLE 7 Prostacyclin and GPIIB/IIa inhibitor Saline n 6 6 Bodyweight g295 301 HGB % change 0-7 hours −23.6% −23.1% PLT % change 0-7 hours  −39%   −70% HR % change 0-7 hours    4.8%   27.6% BP % change 0-7hours    0.7% −20.3%

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1. A method of treating or reducing risk of organ failure, in an acutelyill patient requiring medical intervention to achieve homeostasis;comprising administering to a patient in need thereof one or morecompounds selected from the group consisting of platelet inhibitors,wherein the platelet inhibitor is capable of inhibiting the GPIIb/IIIareceptor and one or more compounds capable of modulating/preserving theendothelial integrity wherein the compound capable ofmodulating/preserving the endothelial integrity is selected from thegroup consisting of PGI2, PGX, nitrogen oxide, and prostacyclin orvariants thereof, thereby treating or preventing organ failure in saidpatient.
 2. The method of claim 1, wherein the platelet inhibitor iscapable of inhibiting the GPIIb/IIIa receptor and the compound capableof modulating/preserving the endothelial integrity is PGI2 or a variantthereof.
 3. The method of claim 1, wherein the platelet inhibitor isselected from the group consisting of abciximab, eptifibatide,tirofiban, orbofiban, xemilofiban, lamifiban, XJ757, DUP728 and XR299.4. The method of claim 1, wherein the platelet inhibitor has a half-lifeof less than 3 hours.
 5. The method of claim 1, wherein the prostacyclinvariant is selected from the group consisting of beraprost sodium,epoprostenol sodium, iloprost, iloprost in combination with bosentan,iloprost in combination with sildenafil citrate, treprostinil, pegylatedtreprostinil, treprostinil diethanolamine and treprostinil sodium,2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide,{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid,8-[1,4,5-triphenyl-1H-imidazol-2-yl-oxy]octanoic acid, isocarbacyclin,cicaprost,[4-[2-(1,1-Diphenylethylsulfanyl)-ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxy]-aceticacid N-Methyl-d-glucamine,7,8-dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-methiminoxy)-ethyl)-a-naphthyloxyaceticacid, (5-(2-diphenylmethyl aminocarboxy)-ethyl)-a-naphthyloxyaceticacid,2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid,[3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid,bosentan, 17[alpha],20-dimethyl-[DELTA]6,6a-6a-carba PGI1, 15-deoxy-16[alpha]-hydroxy-16 [beta],20-dimethyl-[DELTA]6,6a-6a-carba PGI1 andpentoxifylline (1-{5-oxohexyl}-3,7-dimethylxanthine).
 6. The method ofclaim 1, wherein the compound capable of modulating/preserving theendothelial integrity has a half-life of less than 4 hours.
 7. Themethod of claim 1, wherein organ failure is defined as altered organfunction in an acutely ill patient requiring medical intervention toachieve homeostasis; organ failure includes as used herein MOF andTAMOF, in at least one organ.
 8. The method of claim 1, wherein organfailure is defined as altered organ function in an acutely ill patientrequiring medical intervention to achieve homeostasis; organ failureincludes as used herein MOF and TAMOF, in at least one organ, such as inat least two, three, four or five organs, wherein the organ failure isdue to systemic inflammation or due to severe infections or due tosepsis or due to systemic inflammatory response syndrome (SIRS) and/orcompensatory anti-inflammatory response syndrome CARS or due tocoagulopathy or due to trauma and/or burns or due to malignant diseasesor due to ischemia or due to cardiovascular thromboembolic diseases ordue to intoxication.
 9. The method according to claim 1, wherein theorgan or organs which are subject to failure are selected from the groupconsisting of cardiovascular, respiratory, renal, haematological,neurological, gastrointestinal and hepatic organs and musculoskeletal,such as heart, vessels, microvasculature, lungs, kidney, bone marrow,brain, gut, pancreas, spleen, liver, bones, joints and muscles.
 10. Amethod for the preservation of platelet number and/or function in acritically ill patient requiring medical intervention to achievehomeostasis comprising administering to a patient in need thereof one ormore compounds selected from the group consisting of plateletinhibitors, wherein the platelet inhibitor is capable of inhibiting theGPIIb/IIIa receptor, and one or more compounds capable ofmodulating/preserving the endothelial integrity wherein the compoundcapable of modulating/preserving the endothelial integrity is selectedfrom the group consisting of PGI2, PGX, nitrogen oxide, and prostacyclinor variants thereof, thereby treating or reducing risk of organ failurein said patient.
 11. The method of claim 10, wherein the plateletinhibitor is capable of inhibiting the GPIIb/IIIa receptor and thecompound capable of modulating/preserving the endothelial integrity isPGI2 or a variant thereof.
 12. The method of claim 10, wherein theplatelet inhibitor is selected from the group consisting of abciximab,eptifibatide, tirofiban, orbofiban, xemilofiban, lamifiban, XJ757,DUP728 and XR299.
 13. The method of claim 10, wherein the plateletinhibitor has a half-life of less than 3 hours.
 14. The method of claim10, wherein the prostacyclin variant is selected from the groupconsisting of beraprost sodium, epoprostenol sodium, iloprost, iloprostin combination with bosentan, iloprost in combination with sildenafilcitrate, treprostinil, pegylated treprostinil, treprostinildiethanolamine and treprostinil sodium,2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide,{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid,8-[1,4,5-triphenyl-1H-imidazol-2-yl-oxy]octanoic acid, isocarbacyclin,cicaprost,[4-[2-(1,1-Diphenylethylsulfanyl)-ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxy]-aceticacid N-Methyl-d-glucamine,7,8-dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-methiminoxy)-ethyl)-a-naphthyloxyaceticacid, (5-(2-diphenylmethyl aminocarboxy)-ethyl)-a-naphthyloxyaceticacid,2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid,[3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid,bosentan, 17[alpha],20-dimethyl-[DELTA]6,6a-6a-carba PGI1, 15-deoxy-16[alpha]-hydroxy-16 [beta],20-dimethyl-[DELTA]6,6a-6a-carba PGI1 andpentoxifylline (1-{5-oxohexyl}-3,7-dimethylxanthine).
 15. The method ofclaim 10, wherein the compound capable of modulating/preserving theendothelial integrity has a half-life of less than 4 hours.
 16. Themethod of claim 10, wherein organ failure is defined as altered organfunction in an acutely ill patient requiring medical intervention toachieve homeostasis; organ failure includes as used herein MOF andTAMOF, in at least one organ.
 17. The method of claim 10, wherein organfailure is defined as altered organ function in an acutely ill patientrequiring medical intervention to achieve homeostasis; organ failureincludes as used herein MOF and TAMOF, in at least one organ, such as inat least two, three, four or five organs, wherein the organ failure isdue to systemic inflammation or due to severe infections or due tosepsis or due to systemic inflammatory response syndrome (SIRS) and/orcompensatory anti-inflammatory response syndrome CARS or due tocoagulopathy or due to trauma and/or burns or due to malignant diseasessuch as haematological malignancies, solid tumours and metastatictumours or due to ischemia or due to cardiovascular thromboembolicdiseases or due to intoxication.
 18. The method according to claim 10,wherein the organ or organs which are subject to failure are selectedfrom the group consisting of cardiovascular, respiratory, renal,haematological, neurological, gastrointestinal and hepatic organs andmusculoskeletal organs.
 19. A pharmaceutical composition for treating orpreventing organ failure, including multi organ failure, defined asaltered organ function in an acutely ill patient requiring medicalintervention to achieve homeostasis; organ failure includes as usedherein MOF and TAMOF comprising one or more compounds selected from thegroup consisting of platelet inhibitors wherein the platelet inhibitoris capable of inhibiting the GPIIb/IIIa receptor and one or morecompounds capable of modulating/preserving the endothelial integrity,wherein the compound capable of modulating/preserving the endothelialintegrity is selected from the group consisting of PGI2, PGX, nitrogenoxide, and prostacyclin or variants thereof as an active ingredient.